U.S. patent application number 11/910967 was filed with the patent office on 2008-11-13 for methods for treating anxiety related disorders.
This patent application is currently assigned to Hythiam, INC.. Invention is credited to Sanjay Sabnani, Donald Wesson.
Application Number | 20080280885 11/910967 |
Document ID | / |
Family ID | 37087555 |
Filed Date | 2008-11-13 |
United States Patent
Application |
20080280885 |
Kind Code |
A1 |
Sabnani; Sanjay ; et
al. |
November 13, 2008 |
Methods for Treating Anxiety Related Disorders
Abstract
The present invention relates to methods of and compositions for
treating and relieving symptoms and disease associated with
indications caused by a physiological drive to alleviate a
sensation of anxiety. In one treatment method, methods of, and
compositions for, modulating the expression of certain GABAA
receptor subunits are used to treat anxiety-related disorders and
depressive disorders associated with physiological tolerance to
endogenous neurosteroids.
Inventors: |
Sabnani; Sanjay;
(Northridge, CA) ; Wesson; Donald; (Oakland,
CA) |
Correspondence
Address: |
JOHN S. PRATT, ESQ;KILPATRICK STOCKTON, LLP
1100 PEACHTREE STREET
ATLANTA
GA
30309
US
|
Assignee: |
Hythiam, INC.
Los Angeles
CA
|
Family ID: |
37087555 |
Appl. No.: |
11/910967 |
Filed: |
April 7, 2006 |
PCT Filed: |
April 7, 2006 |
PCT NO: |
PCT/US06/13152 |
371 Date: |
April 22, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
60669033 |
Apr 7, 2005 |
|
|
|
60729013 |
Oct 21, 2005 |
|
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60728979 |
Oct 21, 2005 |
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Current U.S.
Class: |
514/220 ;
514/284 |
Current CPC
Class: |
A61P 25/30 20180101;
A61P 43/00 20180101; A61P 25/18 20180101; A61P 25/34 20180101; A61P
1/14 20180101; A61P 25/36 20180101; A61K 31/122 20130101; A61K
31/58 20130101; A61K 31/5517 20130101; A61P 25/22 20180101; A61K
31/137 20130101; A61P 25/00 20180101 |
Class at
Publication: |
514/220 ;
514/284 |
International
Class: |
A61K 31/5517 20060101
A61K031/5517; A61K 31/473 20060101 A61K031/473; A61P 25/00 20060101
A61P025/00 |
Claims
1-26. (canceled)
27. A method of treating an anxiety disorder, an obsessive
compulsive disorder or an eating disorder in a patient comprising
administering to the patient a composition comprising a compound
that modulates GABA.sub.A receptor expression in a pharmaceutically
acceptable carrier.
28. The method of claim 27, wherein the compound is flumazenil or
miltirone.
29. The method of claim 28, wherein the flumazenil is administered
in a therapeutically effective quantity.
30. The method of claim 29, wherein the therapeutically effective
quantity of flumazenil is between 0.5 mg/day and 10 mg/day.
31. The method of claim 28, wherein flumazenil is administered at a
rate of between 0.1 and 0.3 mg over predetermined time intervals
for a total administration of between 0.5 mg/day and 10 mg/day.
32. The method of claim 31, wherein the predetermined time interval
is in the range of 1 and 15 minutes.
33. The method of claim 28, wherein the flumazenil is administered
at a rate of between 0.1 and 0.3 mg over predetermined time
intervals for a total administration of between 1.0 mg/day and 3.0
mg/day.
34. The method of claim 27, further comprising administering a
composition comprising an inhibitor of neurosteroid production in a
pharmaceutically acceptable carrier prior to administering the
composition comprising the compound that modulates GABA.sub.A
receptor expression.
35. The method of claim 34, wherein the inhibitor of neurosteroid
production is a 5-alpha-reductase inhibitor.
36. The method of claim 35, wherein the 5-alpha-reductase inhibitor
is finasteride.
37. The method of claim 36, wherein the finasteride is administered
in an amount of less than 10 mg/day.
38. A method of treating an anxiety disorder in a patient
comprising: assessing the patient for treatment compatibility;
preparing the patient for treatment; and, administering to the
patient a composition comprising a compound that modulates
GABA.sub.A receptor expression in a pharmaceutically acceptable
carrier.
39. The method of claim 38, wherein preparing the patient for
treatment includes withdrawing the patient from current
treatment.
40. The method of claim 38, wherein preparing the patient for
treatment comprises placing the patient in a state of
withdrawal.
41. The method of claim 40, wherein the patient is female and the
female patient is placed in the state of withdrawal by
administering a contraceptive to the patient and then ceasing
administration of the contraceptive.
42. The method of claim 40, wherein the patient is placed in the
state of withdrawal by administering a composition comprising an
inhibitor of neurosteroid production in a pharmaceutically
acceptable carrier.
43. The method of claim 38, wherein the compound is flumazenil or
miltirone.
44. The method of claim 43, wherein the flumazenil is administered
in a therapeutically effective quantity.
45. The method of claim 44, wherein the therapeutically effective
quantity of flumazenil is between 0.5 mg/day and 10 mg/day.
46. The method of claim 43, wherein flumazenil is administered at a
rate of between 0.1 and 0.3 mg over predetermined time intervals
for a total administration of between 0.5 mg/day and 10 mg/day.
47. The method of claim 46, wherein the predetermined time interval
is in the range of 1 and 15 minutes.
48. The method of claim 43, wherein the flumazenil is administered
at a rate of between 0.1 and 0.3 mg over predetermined time
intervals for a total administration of between 1.0 mg/day and 3.0
mg/day.
49. The method of claim 42, wherein the inhibitor of neurosteroid
production is a 5-alpha-reductase inhibitor.
50. The method of claim 49, wherein the 5-alpha-reductase inhibitor
is finasteride.
51. The method of claim 50, wherein the finasteride is administered
in an amount of less than 10 mg/day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention relies on, for priority, U.S.
Provisional Patent Application No. 60/669,033, entitled "Improved
Method for the Treatment of Substance Abuse", filed on Apr. 7,
2005, U.S. Provisional Patent Application No. 60/728,979 entitled
"Methods for the Treatment of Substance Abuse and Dependence",
filed on Oct. 21, 2005, and U.S. Provisional Patent Application No.
60/729,013 entitled "Methods for Treating Anxiety-Related
Diseases", filed on Oct. 21, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of and compositions
for treating and relieving symptoms and disease associated with
indications caused by a physiological drive to alleviate a
sensation of anxiety. More specifically, the present invention
relates to methods of and compositions for treating and relieving
symptoms associated with endogenous neurosteroid withdrawal.
[0003] The present invention is also relates to a methodology for
diagnosing a person in an altered GABA.sub.A receptor state. In
particular, the methodology is directed toward determining the
relative receptivity of a patient to the treatment methodologies of
the present invention by qualitatively or quantitatively measuring
progesterone levels in a patient, or, more preferably, the
allopregnanolone levels within a patient's brain.
[0004] The present invention also relates to a treatment
methodology that, in a first stage, improves a patient's
physiological receptivity to treatment. In particular, the
methodology is directed toward preventing the up-regulation of
endogenous neuroactive steroids or actively down-regulating the
production of endogenous neuroactive steroids to avoid
cross-tolerance. The present invention also relates to optionally
employing conventional treatment programs in combination with the
methods of and compositions of the present invention in a
comprehensive treatment plan.
[0005] The present invention also relates to a treatment
methodology that, in a second stage, employs methods of and
compositions for modulating the expression of certain GABA.sub.A
receptor subunits, thus treating the withdrawal symptoms, such as,
but not limited to, anxiety-related disorders and depressive
disorders associated with physiological tolerance to endogenous
neurosteroids in a comprehensive treatment plan.
[0006] More specifically, the present invention relates to methods
of, devices for, and treatment protocols for using pharmaceutical
compositions from a class of compounds that directly or indirectly
modulates GABA.sub.A by modulating the expression of the GABA.sub.A
receptor .alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit.
[0007] The present invention also relates to a class of compounds,
and methods of identifying such compounds, that modulates the
expression of certain GABA.sub.A receptor subunits. More
specifically, the compound of choice is one that a) acts as a
partial agonist of GABA.sub.A; b) inhibits the upregulation of the
GABA.sub.A receptor .alpha..sub.4 subunit and/or increases the
relative ratio of the GABA.sub.A receptor .alpha..sub.1 subunit to
the GABA.sub.A receptor .alpha..sub.4 subunit; and c) does not
cause the upregulation of the GABA.sub.A receptor .alpha..sub.4
subunit and/or does not cause the decrease of the relative ratio of
the GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit once the composition is no longer
present in the patient's system.
BACKGROUND OF THE INVENTION
[0008] While most anxiety disorders and depressive respond well to
treatment, long-term treatment is conventionally required to
prevent recurrence and maintain anxiety levels. The standard
current approach to treating most anxiety disorders is a
combination of cognitive-behavioral therapy (CBT) with
pharmacological compounds. Typically, the compounds include
selective serotonin reuptake inhibitors (SSRIs) or tricyclic
anti-depressants. Lifestyle changes may include exercise, adequate
rest, and proper nutrition, in addition to measures for relieving
anxiety.
[0009] Drug therapy is sometime disadvantageous because the patient
becomes dependent upon the drug treatment of choice, such as
benzodiazepines or selective serotonin reuptake inhibitors, thus
enhancing stress-related withdrawal symptoms. Also, conventional
methods of treatment fail in that they do not address the
physiochemical changes that occur with anxiety-related
diseases.
[0010] What is therefore needed are improved methods of,
compositions for, and treatment protocols for treating
anxiety-related disorders.
[0011] What is also needed are improved methods of, compositions
for, and treatment protocols for treating anxiety-related
disorders, in which the underlying pathology of the disorder is
addressed.
SUMMARY OF THE INVENTION
[0012] The present invention relates to methods of and compositions
for treating and relieving symptoms and disease associated with
indications caused by a physiological drive to alleviate a
sensation of anxiety. In one treatment method, methods of, and
compositions for, modulating the expression of certain GABA.sub.A
receptor subunits are used to treat or ameliorate anxiety-related
disorders and depressive disorders associated with physiological
tolerance to endogenous neurosteroids.
[0013] More specifically, the present invention relates to methods
of, devices for, and treatment protocols for using pharmaceutical
compositions from a class of compounds that modulates GABA.sub.A by
modulating the expression of the GABA.sub.A receptor .alpha..sub.4
subunit relative to the GABA.sub.A receptor .alpha..sub.1 subunit.
The treatment of choice is one that resets the compositional
profile of the GABA receptor, and more specifically, the GABA.sub.A
subunits, into a normal or a pre-tolerance state.
[0014] The multiple phase treatment methodology of the present
invention employs one or more compounds to reset physiochemical
changes, and thus alleviate a disease state, that are caused by the
brain's unconscious drive to alleviate anxiety arising from the
dysregulation of endogenous neurosteroids.
[0015] In one embodiment, the present invention is directed towards
treating indications that arise from the drive to address an
endogenous neurosteroid "withdrawal". Specifically, diseases such
as generalized anxiety disorder; panic disorder; specific and
social phobias; obsessive compulsive disorder; post-traumatic
stress disorder; and eating disorders, including anorexia nervosa,
bulimia nervosa, and binge eating disorder, have, as part of their
cause, a biologically detrimental physiological and psychological
response to addressing anxiety brought on by endogenous
neurosteroid withdrawal.
[0016] The present invention also provides methods that, in a first
stage, improve an individual's physiological receptivity to
treatment. In particular, the methodology is directed toward
preventing the up-regulation of endogenous neuroactive steroids or
actively down-regulating the production of endogenous neuroactive
steroids to avoid cross-tolerance.
[0017] The present invention also provides methods that, in a
second stage, employs methods of, and compositions for, modulating
the expression of certain GABA.sub.A receptor subunits, thus
treating the withdrawal symptoms associated with psychological and
physiological addiction and dependence in a comprehensive treatment
plan. The present invention also relates to optionally employing
conventional treatment programs in combination with the methods of
and compositions of the present invention in a comprehensive
treatment plan.
[0018] Methods are provided for treating an anxiety disorder by
administering a compound from the class of compounds that modulates
GABA.sub.A receptor expression.
[0019] In one embodiment, the method includes the steps of
assessing a patient for treatment compatibility; preparing a
patient for treatment; and administering a compound from the class
of compounds that modulates GABA.sub.A receptor expression to a
patient.
[0020] Methods are also provided for treating obsessive compulsive
disorder by administering a compound from the class of compounds
that modulates GABA.sub.A receptor expression.
[0021] Methods are also provided for treating an eating disorder by
administering a compound from the class of compounds that modulates
GABA.sub.A receptor expression.
[0022] The present invention also provides a class of compounds,
and methods of identifying such compounds, that modulates the
expression of certain GABA.sub.A receptor subunits. More
specifically, the compound of choice is one that a) acts as a
partial agonist of GABA.sub.A; b) inhibits the upregulation of the
GABA.sub.A receptor .alpha..sub.4 subunit and/or increases the
relative ratio of the GABA.sub.A receptor .alpha..sub.1 subunit to
the GABA.sub.A receptor .alpha..sub.4 subunit; and c) does not
cause the upregulation of the GABA.sub.A receptor .alpha..sub.4
subunit and/or does not cause the decrease of the relative ratio of
the GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit once the composition is no longer
present in the patient's system.
[0023] It is therefore an object of the invention to provide
methods and compositions for inhibiting the formation of
neurosteriods.
[0024] It is another object of the invention to provide methods and
compositions for modulating chloride channels such as GABA.sub.A
receptors.
[0025] It is another object of the invention to provide methods and
compositions for treating symptoms of anxiety-related
disorders.
[0026] Another object of the invention is to provide for the use of
a GABA.sub.A receptor modulator in the preparation of a medicament
to treat an anxiety disorder, obsessive compulsive disorder or an
eating disorder.
[0027] Another object of the invention is to provide for the use of
a neurosteroid production inhibitor in the preparation of a
medicament to treat an anxiety disorder, obsessive compulsive
disorder or an eating disorder.
[0028] These and other objects, features and advantages of the
present invention will become apparent after a review of the
following detailed description of the disclosed embodiments and
claims, and the drawings provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The Detailed Description should be considered in light of
the drawings, as briefly described below:
[0030] FIG. 1 illustrates the spectrum between inhibition and
substantially or completely reduced inhibition via the direct
and/or indirect allosteric modulation of GABA.sub.A;
[0031] FIG. 2 illustrates the internal thought filtering mechanism
in a person's brain;
[0032] FIG. 3a is a first schematic presentation of a plurality of
GABA.sub.A receptor subunits;
[0033] FIG. 3b is a second schematic presentation of a plurality of
GABA.sub.A receptor subunits;
[0034] FIG. 3c is an illustration of the insensitivity of the
modulated GABA.sub.A receptor to benzodiazepines. Note the al
subunit: .alpha.1.beta.2.gamma.2-containing GABA.sub.A receptors
are the most common GABA receptors in the brain.
[0035] FIG. 4 is a chemical diagram of the blockade of the
conversion of progesterone to allopregnanolone via inhibitors of
neurosteroid production.
DETAILED DESCRIPTION OF THE INVENTION
I. Introduction
[0036] Anxiety-related diseases are caused by behavior that arises
from an intense desire to manage and/or avoid anxiety experienced
during endogenous neurosteroid withdrawal. More specifically, the
endogenous neurosteroid allopregnanolone is implicated in the
development and course of various mental and maladaptive disorders.
Allopregnanolone modulates behavioral and biochemical responses to
acute and chronic stress, anxiety, depression, aggressiveness,
convulsions, anesthesia, sleep, memory, pain and feeling, similar
to the effect of GABA. Allopregnanolone acts via at least two
mechanisms, including indirectly by upregulating GABA-binding to
the GABA.sub.A receptor, thus increasing the flow of chloride ions
into the ion channel, or by directly increasing the flow of
chloride ions into the ion channel. The mechanism is described in
greater detail below.
[0037] One method of addressing endogenous neurosteroid withdrawal
is to engage in activities which increase endogenous neurosteroid
production, such as activities which cause stress. Stress activates
adaptive responses and disrupts homeostasis--the brain's internal
balance. Homeostasis can either self-correct allowing the brain to
regain its normal equilibrium, or cause the brain to be in either
an over-aroused or under-aroused state. Allostasis is the term used
to describe these adaptive responses and is further characterized
by the brain's ability to maintain stability or homeostasis through
change. When the systems involved in allostasis do not shut off
when not needed, or do not activate when needed, the brain
experiences a drive to address this inactive or constantly active
state, often exhibited in the form of anxiety or cravings.
[0038] An increase in stress has been shown to increase levels of
endogenous neurosteroids in the body and can sometimes result in
tolerance to the neurosteroid. Anxiety is the result of the
subsequent withdrawal from this increased level of neurosteroids.
While engaging in activities that cause stress do increase the
level of endogenous neurosteroids, this phenomenon can have
detrimental effects on the rest of the body, particularly if the
induced stress is physiologically dangerous, i.e. starvation in the
case of anorexia or vomiting in the case of bulimia. Consequently,
numerous stress-related, anxiety-related or depressive diseases and
disorders may be more accurately characterized as diseases further
characterized and caused by an individual's need to avoid adverse
effects. This loss of inhibitory control contributes to craving and
irrational behavior to engage in activities regardless of
consequences.
[0039] It has been demonstrated that withdrawal from the
neurosteroid 3.alpha.,5.alpha.-allopregnanolone after chronic
administration of progesterone, increases anxiety and up-regulates
the .alpha..sub.4 subunit expression of the GABA.sub.A receptor. In
a non-tolerant subject, the most common GABA.sub.A receptor in the
brain is the .alpha..sub.1.beta..sub.2.gamma..sub.2 receptor, also
referred to as a benzodiazepine sensitive receptor. Upon endogenous
neurosteroid withdrawal or a decrease in the level of progesterone,
the amount .alpha..sub.1 subunits decrease relative to the amount
of .alpha..sub.4 subunits. Withdrawal from the endogenous
neurosteroid often causes symptoms of depression, anxiety and
impulsivity, as GABA uptake is decreased due to the reduced number
of GABA.sub.A receptor .alpha..sub.1 subunits relative to
GABA.sub.A receptor .alpha..sub.4 subunits. Thus, endogenous
neurosteroid regulation, and more specifically, the fluctuation of
allopregnanolone, is implicated in a variety of anxiety disorders
and depressive disorders.
[0040] In one embodiment, the present invention is directed towards
treating indications that arise from the drive to address an
endogenous neurosteroid "withdrawal". Specifically, diseases such
as generalized anxiety disorder; panic disorder; specific and
social phobias; obsessive compulsive disorder; post-traumatic
stress disorder; eating disorders, including anorexia nervosa,
bulimia nervosa, and binge eating disorder; polycystic ovary
syndrome and its related disease states; and metabolic syndrome and
its related disease states, have, as part of their cause, a
biologically detrimental physiological and psychological response
to addressing anxiety brought on by endogenous neurosteroid
withdrawal.
[0041] As mentioned above, certain depressive disorders, including
but not limited to major depressive disorder, dysthymic disorder,
and seasonal affective disorder (SAD), can also be linked to the
fluctuation of allopregnanolone, and have, as part of their cause,
a biologically detrimental physiological and psychological response
to addressing anxiety brought on by endogenous neurosteroid
withdrawal.
[0042] Thus, when the GABA.sub.A receptor is dysregulated, the
clinical manifestation of this dysregulation is initially anxiety.
In addition, the anxiety is often accompanied by compulsive
behavior. Certain compulsive behaviors, such as but not limited to
drug abuse, gambling, compulsive sexual activity, compulsive
eating, and compulsive video game playing, can lead to increased
euphoria, neurosteroid production and brain simulation. Subsequent
discontinuation of these activities can result in withdrawal
syndrome that manifests itself through heightened anxiety and
GABA.sub.A regulator dysregulation.
[0043] Compulsive eating habits may lead to obesity. The compulsion
to eat excessive amounts of food can be attributed, in part, to the
consumption of certain CNS stimulating foods. CNS stimulating foods
result in increased endogenous neurosteroid levels. Both tolerance
to certain foods and subsequent discontinuation of compulsive
eating habits can result in withdrawal syndrome that manifests
itself through heightened anxiety and GABA.sub.A regulator
dysregulation. The tolerance is also associated with an increased
need for a particular food or group of foods to provide CNS
stimulation to increase neurosteroids. It may be possible to
effectively reduce or eliminate this tolerance to certain foods by
treating the anxiety associated with the withdrawal of a particular
food or group of foods. The result of this would be a decreased
need for food which would be beneficial for weight loss.
[0044] Additionally, in treating anxiety associated with caloric
restrictive diets, it may be possible to structure a diet treatment
protocol that enables greater patient compliance. For example, but
not limited to such example, strict dieting guidelines are often an
important component of maintenance treatment post-bariatric
surgery. Bariatric surgery does not address the underlying
physiology behind compulsive eating, but rather, the physical
symptomatology. Reducing or eliminating the tolerance associated
with certain foods by treating the anxiety associated withdrawal
from these foods is one method of maintaining patient compliance
post-bariatric surgery.
[0045] In addition, certain neurodegenerative disorders can be
related to GABA.sub.A receptor dysregulation. GABA.sub.A receptor
dysregulation, in one embodiment, causes the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the
.alpha..sub.1 subunit. The .alpha..sub.4 subunit-containing
GABA.sub.A receptor is less sensitive to the effects of GABA. As a
result, tonic levels of GABA may increase, leading to neuronal
apoptosis and deafferation of specialized brain cells. The result
may be a neurodegenerative disorder, including, but not limited to
Alzheimer's disease, age-related dementia, schizophrenia, and
Parkinson's disease.
[0046] The present invention is thus directed towards methods of
and compositions for treating and relieving symptoms and disease
associated with indications caused by a physiological drive to
alleviate a sensation of anxiety. More specifically, the present
invention is directed towards methods of and compositions for
treating and relieving symptoms associated with endogenous
neurosteroid withdrawal.
[0047] The present invention is also directed towards a methodology
for diagnosing a person in an altered GABA.sub.A receptor state. In
particular, the methodology is directed toward determining the
relative receptivity of a patient to the treatment methodologies of
the present invention by qualitatively or quantitatively measuring
progesterone levels in a patient, or, more preferably, the
allopregnanolone levels within a patient's brain.
[0048] The present invention is also directed towards a treatment
methodology that, in a first stage, improves a patient's
physiological receptivity to treatment. In particular, the
methodology is directed toward preventing the up-regulation of
endogenous neuroactive steroids or actively down-regulating the
production of endogenous neuroactive steroids to avoid
cross-tolerance.
[0049] In one embodiment the present invention is directed towards
optionally employing conventional treatment programs prior to or in
conjunction with the methods of and compositions of the present
invention in a comprehensive treatment plan.
[0050] The present invention is also directed towards a treatment
methodology that, in a second stage, employs methods of and
compositions for modulating the expression of certain GABA.sub.A
receptor subunits, thus treating the withdrawal symptoms, such as
anxiety-related disorders and depressive disorders, associated with
physiological tolerance to endogenous neurosteroids.
[0051] More specifically, the present invention is directed towards
methods of, devices for, and treatment protocols for using
pharmaceutical compositions from a class of compounds that directly
or indirectly modulates GABA.sub.A by modulating the expression of
the GABA.sub.A receptor .alpha..sub.4 subunit relative to the
GABA.sub.A receptor .alpha..sub.1 subunit.
[0052] The present invention is also directed towards a class of
compounds, and methods of identifying such compounds, that
modulates the expression of certain GABA.sub.A receptor subunits.
More specifically, the compound of choice is one that a) acts as a
partial agonist of GABA.sub.A; b) inhibits the upregulation of the
GABA.sub.A receptor .alpha..sub.4 subunit and/or increases the
relative ratio of the GABA.sub.A receptor .alpha..sub.1 subunit to
the GABA.sub.A receptor .alpha..sub.4 subunit; and c) does not
cause the upregulation of the GABA.sub.A receptor .alpha..sub.4
subunit and/or does not cause the decrease of the relative ratio of
the GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit once the composition is no longer
present in the patient's system.
II. The GABAergic System
[0053] a. Gamma-Aminobutyric Acid (GABA)
[0054] GABA is a neurotransmitter that acts at inhibitory synapses
in the brain and spinal cord. The GABA system is found, among other
places, in the hippocampus, an area of the brain associated with
memory formation. Glutamic acid, or glutamate, is important in
brain function, as an excitatory neurotransmitter and as a
precursor for the synthesis of GABA in GABAergic neurons. Glutamate
activates both ionotropic and metabotropic glutamate receptors,
described in further detail below. GABA signals interfere with
registration and consolidation stages of memory formation.
[0055] b. GABA Receptor Types
[0056] The GABA receptors are a group of receptors with GABA as
their endogenous ligand. Several classes of GABA receptors are
known, including ionotropic receptors, which are ion channels
themselves, and metabotropic receptors, which are G-protein coupled
receptors that open ion channels via intermediaries. Glutamate and
GABA mediate their actions by the activation of their
receptors.
[0057] The ionotropic GABA receptors (GABA.sub.A receptors) are
based on the presence of eight subunit families consisting of 21
subunits (.alpha..sub.1-6, .beta..sub.1-4, .gamma..sub.1-4,
.delta., .epsilon., .pi., .theta., .rho..sub.1-3) and display an
extraordinarily structural heterogeneity. GABA.sub.A receptors are
composed of five circularly arranged, homologous subunits and are
important sites of drug action. Most often, the GABA.sub.A receptor
isomers comprise two .alpha. subunits, two .beta. subunits and one
.gamma. subunit. The metabotropic GABA receptors (GABA.sub.B
receptors) consist of two subunits: GABA.sub.B1 and GABA.sub.B2.
Physiological responses following activation of GABA.sub.B
receptors require the co-assembly of GABA.sub.B1 and GABA.sub.B2.
GABA.sub.C receptors also exist natively.
[0058] c. GABA.sub.A Receptor Subunits
[0059] The GABA.sub.A receptor system is implicated in a number of
central nervous system disorders, making GABA.sub.A receptor
ligands potential therapeutic agents. GABA.sub.A receptors are
ligand-gated ion channels that belong to the same super family of
receptors as glycine, nicotinic cholinergic, and serotonin
5HT.sub.3 receptors. Enhanced function of several GABA.sub.A
receptors accounts for the major actions of benzodiazepines,
described in greater detail below. In addition, a number of
compounds have exhibited functional selectivity for GABA.sub.A
receptors.
[0060] The GABA.sub.A receptor complex is a pentameric receptor
protein structure formed by co-assembly of subunits from seven
different classes. Five subunits are situated in a circular array
surrounding a central chloride-permeable pore. It has been
suggested that the mechanism for ligand-induced channel opening in
nicotinic acetylcholine receptors involves rotations of the
subunits in the ligand binding domain. Assuming that GABA.sub.A
receptors utilize a similar mechanism for channel opening, since
GABA.sub.A receptors belong to the same super family as the
nicotinic acetylcholine receptors, large substituents may interfere
with the channel opening (steric hindrance) resulting in
antagonistic effects of certain compounds. In addition, the
activation of GABA receptors will influence several other systems,
ultimately resulting in a general acute modification of the overall
function of the central nervous system.
[0061] The particular combination of subunits yields receptors with
different pharmacological and physiological properties, however,
the GABA.sub.A receptor composition is not immutable. Withdrawal
from anxiolytic benzodiazepines, which produce their effects by
facilitating GABA.sub.A receptor mediated inhibition, yields an
increase in the steady state mRNA levels of .alpha..sub.4 and
.beta..sub.1 subunit mRNA in both the cortex and hippocampus. It
should be noted that the 8 subunit is often associated with
GABA.sub.A receptor subtypes containing the .alpha..sub.4
subunit.
[0062] GABA and GABA.sub.A receptors are involved in disease states
such as seizures, depression, anxiety and sleep disorders. GABA and
some of the other indirectly or directly acting GABA.sub.A receptor
agonists (GABA-mimetics), including allopregnanolone and
tetrahydrodeoxycorticosterone respectively, bind specifically to a
recognition site located at the interface between an .alpha. and a
.beta. subunit. The classical benzodiazepines, however, such as
diazepam and flunitrazepam, bind to an allosteric site located at
the interface between an .alpha. and a .gamma. subunit.
[0063] More specifically, GABA binds to the cleft between .alpha.
and .beta. subunits, an action which gates open the chloride
channel to allow for the influx of chloride ions into the cell.
This typically hyperpolarizes the cell, having an inhibitory action
on neuronal activity, by making the membrane potential of the cell
more negative, and consequentially, increases the depolarization
threshold to generate an action potential.
[0064] Most depressant and sedative drugs such as the
benzodiazepine tranquilizers, barbiturates, anesthetics and alcohol
are believed have a modulatory effect on the GABA.sub.A receptor at
unique sites where they can enhance the actions of GABA in
accumulating negatively charged chloride ions into the cell,
inducing sedative or anesthetic effects.
[0065] The conformational restriction of various parts of the
molecule of GABA and biosteric replacements of the functional
groups of the amino acid leads to a broad spectrum of specific
GABA.sub.A agonists. Some of these molecules have played a key role
in the understanding of the pharmacology of the GABA.sub.A receptor
family.
[0066] The absence or presence of a particular .alpha. subunit
isoform in the GABA.sub.A receptors confers selectivity for certain
drugs. Different .alpha. subunits also mediate distinct
pharmacological actions of benzodiazepines, including
sedative-hypnotic and anxiolytic effects. Long-term administration
of benzodiazepines results in the development of tolerance to some
of the effects of these drugs, thus reducing their clinical
efficacy. While the molecular basis for these dependencies remains
unclear, tolerance and dependence appear to be related to the
pharmacodynamics of benzodiazepines.
[0067] Long-term administration of benzodiazepines modifies the
expression of genes that encode various GABA.sub.A subunits. These
changes in gene expression alter the sensitivity of GABA.sub.A
receptors to their pharmacological modulators and thereby underlie
the development of tolerance to or dependence on these drugs. The
subunit composition of GABA.sub.A receptor determines their
affinity for benzodiazepine receptor ligands as well as the
efficacy of these ligands. For example, classical benzodiazepine
agonists (e.g. diazepam), imidazopyridines, imidazoquinolones and
pyrazolopyrimidines show no affinity for or efficacy at GABA.sub.A
receptors that contain .alpha..sub.4 or .alpha..sub.6 subunits.
[0068] The subunit composition of native GABA.sub.A receptors plays
an important role in defining their physiological and
pharmacological function. It is possible to characterize the
physiological, pharmacological, and pathological roles of
GABA.sub.A receptors by understanding the mechanisms by which the
subunit composition of GABA.sub.A receptors is regulated. Thus, the
expression of specific GABA.sub.A receptor subunit genes may be
affected by various physiological and pharmacological modulators,
including but not limited to, pharmacological agents, endogenous
neurosteroids, and food.
[0069] For example, long-term exposure to and subsequent withdrawal
of benzodiazepines, zalpelon, zolpidem, or neurosteroids result in
selective changes in the expression of specific GABA.sub.A receptor
mRNA, including an increase of the .alpha..sub.4 subunit mRNA, and
polypeptide subunits and in GABA.sub.A receptor function in
cultured cells. Withdrawal from diazepam or imidazenil was
associated with both a reduced ability of diazepam to potentiate
GABA action and the ability of flumazenil to potentiate GABA
action. Chronic benzodiazepine treatment and subsequent withdrawal
lead to a change in the receptor subunit composition, and these new
synthesized receptors are less responsive to benzodiazepines. The
up-regulation of the .alpha..sub.4 subunit, however, may be
necessarily coupled with the down-regulation of other subunits for
the development of benzodiazepine dependence.
[0070] Withdrawal of zalpelon or zolpidem, like that of diazepam,
induced a marked increase in the amount of .alpha..sub.4 subunit
mRNA. These effects of zalpelon and zolpidem on GABA.sub.A receptor
gene expression are consistent with the reduced tolerance liability
of these drugs, compared with that of diazepam, as well as with
their ability to induce both physical dependence and withdrawal
syndrome.
[0071] Ethanol withdrawal-induced increases in the amounts of
.alpha..sub.4 subunit mRNA and protein are associated with reduced
sensitivity of GABA.sub.A receptors to GABA and benzodiazepines.
The effects of alcohol are similar to those of drugs that enhance
the function of GABA.sub.A receptors, which gate the Cl-- currents
that mediate most inhibitory neurotransmission in the brain, as
described above. Acutely high doses of alcohol potentiate
GABA-gated currents at both native and recombinant GABA.sub.A
receptors, and chronically alter GABA.sub.A receptor expression.
Ethanol elicits its central effects through modulation of
neurotransmission mediated by various receptors, especially that
mediated by GABA.sub.A receptors. It has been shown that long-term
ethanol administration also affects the subunit composition and,
consequently, the functional properties of native GABA.sub.A
receptors. The pharmacological profile of ethanol is similar to
that of benzodiazepine and also results in the development of
cross-tolerance and dependence.
[0072] Exposure to diazepam at the time of ethanol withdrawal
antagonizes the withdrawal-induced increase in the abundance of the
.alpha..sub.4 subunit mRNA. The replacement of ethanol with
diazepam also blocked the ethanol withdrawal-induced impairment in
cellular metabolism. Cells exposed to GHB at the time of ethanol
withdrawal results in an inhibition in the increase in the
abundance of the .alpha..sub.4 subunit mRNA.
[0073] The modulatory action of flumazenil in cells that are
exposed to ethanol is similar to that measured in cells not exposed
to ethanol. In contrast, however, in ethanol withdrawn cells, 3
.mu.M flumazenil potentiates the GABA evoked Cl-- current
consistent with the ethanol withdrawal-induced up-regulation of the
.alpha..sub.4 subunit in these cells. The substitution of 10 .mu.M
diazepam or 100 mM GHB for ethanol negated the positive modulation
of 3 .mu.M flumazenil induced by ethanol withdrawal.
[0074] The presence of the .alpha..sub.4 subunit in recombinant
GABA.sub.A receptors is associated with a reduced sensitivity to
classical benzodiazepine agonists and to zolpidem as well as with a
distinct pattern of regulation (positive rather than no allosteric
modulation) by flumazenil.
[0075] In general, chronic treatment with agonists that act at
different sites of the GABA.sub.A receptor results in changes in
the biochemical and functional properties of the receptor that are
accompanied by changes in the abundance of specific receptor
subunit mRNAs. In addition, chronic treatment with substances that
modulate GABA.sub.A function via a neurosteroid pathway results in
changes in the biochemical and functional properties of the
receptor that are accompanied by changes in the abundance of
specific receptor subunit mRNAs. The observation that the ethanol
withdrawal-induced increase in the expression of the .alpha..sub.4
subunit gene in cultured cerebellar granule cells is prevented by
diazepam is consistent with the fact that benzodiazepine treatments
are effective in treating alcohol withdrawal symptoms in humans.
Thus, a rapid and marked increase in the abundance of the
.alpha..sub.4 subunit induced by ethanol withdrawal might therefore
contribute to the development of diazepam-sensitive withdrawal
symptoms in humans.
III. GABA and Neurosteroids
[0076] Characterizations of the role of GABA.sub.A receptors
require an understanding of the mechanisms by which subunit
composition is regulated. The long-term administration of
sedative-hypnotic, anxiolytic, or anticonvulsant drugs can affect
expression of GABA.sub.A receptor subunit genes as well as the drug
sensitivity and function of these receptors, suggesting that the
mechanisms responsible for such changes might also underlie the
physiological modulation of GABA.sub.A receptors by endogenous
compounds such as neurosteroids.
[0077] The neuroactive steroids
3.alpha.-hydroxy-5.alpha.-pregnan-20-one (allopregnanolone) and
3.alpha.,21-dihydroxy-5.alpha.-pregnan-20-one
(allotetradihydrodeoxycorticosterone, or THDOC) induce anxiolytic,
sedative, hypnotic, and anticonvulsant effects similar to
benzodiazepines and other anxiolytic drugs. The concentrations of
these neurosteroids are increased in the brain of humans both in
response to treatment with anxiogenic, antidepressant or
antipsychotic drugs as well as physiological or pathological
conditions (such as depression, stress, the luteal phase of the
menstrual cycle, and pregnancy) that affect mood and emotional
state. Additional studies implicate endogenous allopregnanolone as
a physiological regulator of both basal and stress-induced dopamine
release in the rat brain.
[0078] Steroid metabolites react with the GABA receptor complex to
alter brain excitability. Several of these steroids accumulate in
the brain after local synthesis or after metabolism of adrenal
steroids. Neurosteroids are synthesized in the peripheral and
central nervous system, from cholesterol or steroidal precursors
imported from peripheral sources. Both progesterone and estrogen
alter excitability of neurons of the central nervous system. For
example, estrogen reduces inhibition at the GABA.sub.A receptor,
enhances excitation at the glutamate receptor, and increases the
number of excitatory neuronal synapses. In contrast, progesterone
enhances GABA-mediated inhibition, increases GABA synthesis, and
increases the number of GABA.sub.A receptors. In particular,
progesterone and its metabolites have been demonstrated to have
profound effects on brain excitability. The levels of progesterone
and its metabolites vary with the phases of the menstrual cycle,
decreasing prior to the onset of menses. Progesterone is readily
converted to allopregnanolone (3.alpha.-OH-5.alpha.-pregnan-20-one
or 3.alpha.,5.alpha.-THP) in human brains. Allopregnanolone-induced
GABA.sub.A receptor dysregulation has been closely linked to major
anxiety-related diseases, thus linking anxiety to allopregnanolone
"withdrawal".
[0079] Neurosteroids rapidly alter neuronal excitability thorough
interaction with neurotransmitter-gated ion channels.
Allopregnanolone is a positive potent modulator of the GABA.sub.A
receptor and enhances the action which gates open the chloride
channel to allow influx of chloride ions into the cell. This
typically hyperpolarizes the cell, having an inhibitory action on
neuronal activity, and thus allopregnanolone acts as a sedative or
anxiolytic agent and decreases anxiety.
[0080] GABA.sub.A-modulatory allopregnanolone, as described above,
is also responsible for producing anxiogenic withdrawal symptoms.
The withdrawal profile shown therein is similar to that reported
for other GABA.sub.A-modulatory drugs such as the benzodiazepines,
barbiturates, and ethanol. Thus, the actions of neuroactive
steroids on traditional transmitter receptor in the brain lead to
alterations in the GABA.sub.A receptor subunit composition that
result in changes in the intrinsic channel properties of the
receptor and behavioral excitability. Changes are also associated
with significant increases in both the mRNA and protein for the
.alpha..sub.4 subunit of the GABA.sub.A receptor in the
hippocampus. It has also been demonstrated that chronic
administration of progesterone inhibits the upregulation of the
.alpha..sub.4 subunit of the GABA.sub.A receptor and/or suppresses
receptor activity.
[0081] Thus, the endogenous neurosteroid allopregnanolone exhibits
withdrawal properties, similar to GABA-modulators such as
tranquilizers and alcohol, as described above, increasing anxiety
susceptibility following abrupt discontinuation after chronic
administration. The increase in neuronal excitability has been
attributed to upregulation of the GABA.sub.A .alpha..sub.4 subunit.
Thus, the .alpha..sub.4.beta..sub.2.gamma. is preferentially
expressed following hormone withdrawal. Blockade of the .alpha.4
gene transcript prevents withdrawal properties.
[0082] The increase in expression of the GABA.sub.A receptor
.alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit can thus be attributed to many factors. These
include, but are not limited to 1) compositions, both endogenous
and exogenous, which, upon withdrawal, increase the GABA.sub.A
receptor .alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit; and 2) compositions, both exogenous or
endogenous that result in the increase of expression of the
GABA.sub.A receptor .alpha..sub.4 subunit or the decrease of
expression of the GABA.sub.A receptor .alpha..sub.1 subunit.
[0083] Certain substances, both endogenous and exogenous, can cause
modifications in the allostatic control of GABA.sub.A, directly or
indirectly, via an endogenous neurosteroid pathway. Most substances
that cross the blood-brain barrier in sufficient quantity can
stimulate a neuroprotective, neurosteroid response. In general, the
more neuroexcitatory the substance, the more neurosteroid response
is achieved. With the up-regulation of neurosteroids, GABA.sub.A
receptor activity is enhanced, causing a constant state of
activation which, over time, may cause neurosteroid tolerance.
Therefore, once the neuroexcitatory substance is no longer present,
the brain's neurosteroid levels will decrease to natural levels,
causing the individual to go through a state of "withdrawal" from
the neurosteroid.
[0084] In the course of this "withdrawal", certain GABA.sub.A
receptor subunits may be expressed, or suppressed, in a manner that
causes the person's brain to be susceptible to greater feelings of
anxiety. In particular, his brain's GABA.sub.A receptor
.alpha..sub.1 subunits decrease in relative amounts to GABA.sub.A
receptor .alpha..sub.4 subunits. As a result of neurosteroid
"withdrawal" and the subsequent up-regulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits, the GABA receptor is
no longer effectively modulated by GABA, and, therefore, results in
the person experiencing a greater sense of anxiety.
[0085] In one embodiment, an individual's lowered degree of
inhibitory control over his thoughts is caused by the modification
of the receptivity of the synaptic GABA.sub.A receptors to the
neurotransmitter GABA in the individual's brain. For example,
substance abuse diminishes GABA receptivity; thus, the exogenous
substance or "drug" modulates the GABA.sub.A receptor. When the
user ceases consumption of the exogenous substance, due to changes
in the GABA.sub.A receptor composition upon withdrawal (i.e.
increased relative amount of GABA.sub.A receptor .alpha..sub.4
subunits compared to GABA.sub.A receptor .alpha..sub.1 subunits),
the receptor is not effectively modulated by GABA, thus causing
anxiety.
[0086] FIG. 1 illustrates the spectrum between inhibition and
disinhibition via the direct and/or indirect allosteric modulation
of GABA.sub.A. Spectrum 100 further depicts the range between
inhibition 105 and disinhibition 110. An increase in an exogenous
or endogenous substance that directly or indirectly enhances the
function of GABA or the GABA.sub.A receptor 115 can result in an
increase in GABA agonism and thus an increase in inhibition,
anxiolysis, amnesia, and sedation, and even a comatose state.
[0087] However, as mentioned in greater detail above, stress, drug
use, and even behavior activates these adaptive responses and
disrupts homeostasis--the brain's internal balance. Upon withdrawal
of both endogenous and exogenous substances, there is a marked
increase in the .alpha..sub.4 subunit 120 of relative to the
.alpha..sub.1 subunit 125 of the GABA.sub.A receptor 115, as shown
in spectrum 150. The increase of the .alpha..sub.4 subunit 120 of
the GABA.sub.A receptor 115 causes the receptor to become
insensitive to benzodiazepines and other compositions that act upon
and/or enhance the function of GABA and the GABA.sub.A receptor.
Therefore, when the systems involved in allostasis do not
self-regulate (i.e. do not shut off when not needed or do not
activate when needed), the brain experiences a compensatory drive
to address this inactive or constantly active state, often
exhibited in the form of anxiety or cravings.
IV. Anxiety and Inhibition
[0088] Anxiety may be defined in a plurality of ways, including a
vague unpleasant emotion that is experienced in anticipation of
some, often ill-defined misfortune, a complex combination of the
feeling of fear, apprehension and worry often accompanied by
physical sensations such as palpitations, chest pain and/or
shortness of breath, a feeling of apprehension, fear, nervousness,
or dread accompanied by restlessness or tension, and/or a
debilitating condition of fear, which interferes with normal life
functions. Anxiety is evaluated clinically using diagnostic
inventories such as the Hamilton Anxiety Rating Scale (Guy,
William, "048 HAMA Hamilton Anxiety Scale," ECDEU Assessment
Manual, U.S. Department of Health and Human Services, Public Health
Service--Alcohol, Drug Abuse, and Mental Health Administration,
Rev. 1976, pp. 194-198) or the Beck Anxiety Inventory (Encephale.
1994 January-February; 20(1): 47-55), which are herein incorporated
by reference.
[0089] In one embodiment, anxiety comprises a physiological state
in which an individual has a lowered degree of inhibitory control
over his thoughts, as described above with respect to FIG. 1. Such
lowered degree of inhibitory control may be caused by the turning
off, inhibition, or otherwise down-modulation of an internal
thought filtering mechanism in the person's brain. Referring to
FIG. 2, the internal thought filtering mechanism 200 comprises
certain centers within a person's prefrontal cortex 205, including
the orbitofrontal cortex 210, which is considered responsible for
exerting control, and the anterior cingulate 215, which is
considered responsible for motivation and drive impulses. These
brain centers are substantially affected by certain physiological
inputs, such as a reward circuit that comprises the nucleus
accumbens 220 and ventral tegmental 225 areas of the brain.
[0090] When normally regulated, the orbitofrontal cortex 210 can
exert control over a person's thoughts and avoid having an
individual feel "overwhelmed" by vague, unpleasant emotions and
feelings of fear, apprehension and worry. If GABA.sub.A receptor
functionality is somehow impaired, however, GABA dysregulation
occurs and can result in an impaired ability of the orbitofrontal
cortex 210 to exert control over a person's thoughts and,
therefore, a lowered degree of inhibitory control.
[0091] Consequently, the individual becomes compulsively driven to
"address" this anxiety by making sure he obtains whatever
substance, or engage in whatever activity, his brain believes it
needs in order to eliminate the feelings of anxiety, e.g. regain
inhibitory control over his thoughts. Therefore, it is the
physiological drive to address feelings of anxiety that causes an
individual to consciously engage in behavior which could be
classified as self-destructive, such as substance abuse.
[0092] In the absence of a solution to address anxiety, a person is
in a constant stress response state which, both psychologically and
physiologically, directs the person to search for and obtain a
solution to the anxiety. Many indications are implicated as being
caused by the physiological drive to address feelings of anxiety.
As discussed below, certain indications are caused by the
psychological addiction and physiological dependence upon various
substances, both exogenous and endogenous.
[0093] Exogenous substances, such as opioids, benzodiazepines,
cannabis, caffeine, nicotine, and other drugs, directly or
indirectly affect GABA.sub.A receptor functionality and, when those
exogenous substances are withheld from an individual, cause the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit
(hereinafter generally referred to as the .alpha..sub.4 subunit) to
increase relative to the expression of the .alpha..sub.1
subunit.
[0094] In particular, during use, such substances may directly or
indirectly stimulate GABA.sub.A via a neurosteroid mediated
pathway. When those substances are later withheld, the amount of
.alpha..sub.4 subunits relative to .alpha..sub.1 subunits
increases. This ratio change is often temporary and is subject to
reversal. However, a distinct pathophysiology emerges when it
becomes non-reversing, namely when .alpha..sub.4 subunits no longer
down-regulate relative to .alpha..sub.1 subunits. As described
above, when such pathophysiology gets established, the GABA.sub.A
receptor therefore becomes less sensitive to benzodiazepines and
effectively, modulation by the neurotransmitter GABA, and is less
capable of exerting inhibitory control over an individual's
thoughts and behavior.
[0095] In one embodiment, it is possible to calculate a GABA-active
steroid score ("GS Score") for nearly all substances. For every
substance that crosses the blood brain barrier, or is active on the
central nervous system, there is a minimum threshold level needed
of that particular substance to effectively raise levels of
GABA-active steroids. Thus, the GS Score correlates direct agonism
of GABA.sub.A and the indirect modulation of GABA.sub.A via a
neurosteroid mediated pathway, such as, but not limited to
allopregnanolone. For example, but not limited to such example,
cocaine has a lower GS Score than aspartame, since cocaine is more
potent and it takes a lower threshold dose of cocaine to raise
levels of GABA-active steroids. The GS Score is a methodology for
measuring and assigning a numeric value to the relative addictive
properties of substances.
[0096] Referring to FIG. 3a, a benzodiazepine sensitive GABA.sub.A
receptor 300a is shown. The GABA.sub.A receptor comprises a
plurality of subunits, including two .beta..sub.2 subunits 305a, a
.gamma..sub.2 subunit 310a, and two .alpha..sub.1 subunits 315a. By
affecting the functionality and expression of receptor subunit
mRNAs, certain endogenous and exogenous substances cause the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit to
increase relative to the expression of the .alpha..sub.1 subunit.
Referring to FIG. 3b, the modified GABA.sub.A receptor 300b
comprises a plurality of subunits, including two .beta..sub.2
subunits 305b, a .gamma..sub.2 subunit 310b, and two .alpha..sub.4
subunits 315b. As shown in FIG. 3c, the GABA.sub.A receptor
therefore becomes less sensitive to benzodiazepines and
effectively, modulation by the neurotransmitter GABA, and is less
capable of exerting inhibitory control over an individual's
thoughts and behavior.
[0097] Endogenous substances may also have similar effects.
Specifically, GABA-modulatory steroids, such as progesterone and
deoxycorticosterone (DOC) and their metabolites allopregnanolone
and tetrahydrodeoxycorticosterone respectively, affect GABA.sub.A
receptor functionality and thus, when progesterone or DOC is
decreased or "withdrawn" in an individual, cause the expression of
the GABA.sub.A receptor .alpha..sub.4 subunit to increase relative
to the expression of the .alpha..sub.1 subunit.
[0098] In addition, an increase in the level of endogenous
neurosteroid is associated with tolerance. Thus, engaging in
activities that increase neurosteroid production is an often
temporary solution, because as described above, a distinct
pathophysiology emerges and when it becomes non-reversing, namely
when .alpha..sub.4 subunits no longer down-regulate relative to al
subunits. This loss of inhibitory control impairs an individual's
ability to act on cravings and thus contributes to irrational
behavior to engage in activities regardless of consequences.
[0099] Many systems within the body are subject to inhibitory
control via GABAergic neurons located in the brain. In the event
that an endogenous system is subject to inhibitory feedback by
GABA, then the dysregulation of GABAa receptors can result in
reduced inhibition or disinhibition of that particular system.
Thus, it can be determined whether a primary system is
dysregulated, and thus disinhibited, often noted because a patient
exhibits a particular indication or disease state, and more
specifically, a disease state where higher levels of an endogenous
marker are present. For example, but not limited to such example,
abnormal cholesterol levels are indicative of dysregulation of a
primary system. If, however, a primary system is not dysregulated,
then it can be determined whether an inhibitory system is
disinhibited or dysregulated, and whether that inhibitory system is
restored in the presence of endogenous neurosteroids, such as
allopregnanolone and progesterone.
[0100] For example, but not limited to such example, prolactin
inhibits dopamine, and thus when a patient presents with lower
levels of dopamine, it is suggested that prolactin is not being
subjected to inhibitory feedback, resulting in increased levels of
prolactin. Increased levels of prolactin may be, at least in part,
due to GABA.sub.A receptor dysregulation, and thus
disinhibition.
V. Compositions Used in the Novel Treatment Methodologies of the
Present Invention
[0101] The compositions described herein, and the compounds
identified through the screening methodologies described herein,
are intended to be used as drugs in the treatment methodologies
described below. As used in this description, the term drug is used
to refer to prescription or non-prescription pharmaceutical
compositions and/or medications that include an active ingredient
and, optionally, non-active, buffering, or stabilizing ingredients,
including pharmaceutically acceptable carriers or excipients
suitable for the form of administration of said pharmaceutical
compositions. It should be appreciated that the administration of
the drug may be achieved through any appropriate route of
administration, for example, orally, inhaled, anally, sublingual,
bucally, transdermally, nasally, implant or parenterally, for which
it will be formulated using the appropriate excipients for the form
of administration.
[0102] Table 1 offers an exemplary listing of pharmacological
compounds in the classes of compounds described herein. It should
be noted however, that Table 1 is not an exhaustive list of all of
the compositions that can be used with the present invention and
that the present invention is not limited to the use of such
compounds.
[0103] a. Compounds that Inhibit Neurosteroid Production
[0104] In one embodiment, the present invention is directed towards
a method of using a compound from a class of compounds that inhibit
neurosteroid production ("Inhibitors of Neurosteroid Production").
In one embodiment, the compound is one that inhibits the conversion
of progesterone to its metabolite allopregnanolone. In another
embodiment, the compound is one that inhibits the conversion of
progesterone metabolite 5.alpha.-dihydroprogesterone into
allopregnanolone.
[0105] As shown in FIG. 4, progesterone is first converted to
5.alpha.-dihydroprogesterone via an enzyme called
5.alpha.-reductase. 5.alpha.-dihydroprogesterone is then converted
to 5.alpha.,3.alpha.-pregnanolone (allopregnanolone) via the
3.alpha.-hydroxysteroid oxidoreductase enzyme.
[0106] Reference will now be made to specific classes of inhibitors
of neurosteroid production for use in the present invention. While
the classes and inhibitors of neurosteroid production are described
generally herein, it should be understood to those of ordinary
skill in the art that any number of inhibitors of neurosteroid
production that prevent the conversion of progesterone into its
metabolite allopregnanolone can be used in the present invention
and that the list is not exhaustive.
[0107] In one embodiment, an individual is administered a
therapeutically effective amount of a 5-alpha-reductase inhibitor
which blocks the conversion of progesterone into allopregnanolone.
One exemplary 5-alpha-reductase inhibitor is finasteride or analogs
or derivatives thereof. Preferably, the 5.alpha.-reductase
inhibitor is capable of acting as a Type I inhibitor, a Type II
inhibitor, or a combination thereof, and inhibits the
5.alpha.-reductase enzyme from converting progesterone to
5.alpha.-dihydroprogesterone and thus from creating progesterone
metabolite allopregnanolone.
[0108] There are currently accepted dosing regimens for
5-alpha-reductase inhibitors. The present invention contemplates
operating within the maximum limits of currently accepted dosing
regimens in order to maximally decrease the production of
allopregnanolone and make the individual most receptive to
treatment.
[0109] In one embodiment, an individual is administered a
therapeutically effective amount of a 3-alpha-hyrodxysteroid
oxidoreductase inhibitor which blocks the conversion of
progesterone metabolite 5.alpha.-dihydroprogesterone into
allopregnanolone. One exemplary 3-alpha-hyrodxysteroid
oxidoreductase is indomethacin or analogs or derivatives thereof.
There are currently accepted dosing regimens for
3-alpha-hyrodxysteroid oxidoreductase inhibitors. The present
invention contemplates operating within the maximum limits of
currently accepted dosing regimens in order to effectively decrease
the production of allopregnanolone and make the individual most
receptive to treatment.
[0110] Bitran et al (1995) have demonstrated that treatment with a
5-alpha-reductase inhibitor prevents the conversion of progesterone
to allopregnanolone and eliminates the anxiolytic activity of
progesterone. In addition, it has been suggested that the
anxiogenic withdrawal properties of allopregnanolone can be
prevented by previous administration of a 3.alpha.-hydroxysteroid
oxidoreductase blocker such as indomethacin.
[0111] i. 5.alpha.-Reductase Inhibitors
[0112] The 5.alpha.-reductase inhibitors are a group of drugs with
anti-androgenic activity that effectively decrease the amount of
the 5.alpha.-reductase enzyme and thus inhibit neurosteroid
production.
[0113] 1. Finasteride
[0114] Finasteride is a synthetic 4-azasteroid compound, and is a
5alpha-reductase inhibitor. Finasteride is
4-azaandrost-1-ene-17-carboxamide,
N-(1,1-dimethylethyl)-3-oxo-,(5.alpha.,17.beta.)-. The empirical
formula of finasteride is C.sub.23H.sub.36N.sub.2O.sub.2 and its
molecular weight is 372.55.
[0115] Finasteride is a competitive and specific 5.alpha.-reductase
inhibitor. Finasteride has no affinity for the androgen receptor
and has no androgenic, antiandrogenic, estrogenic, antiestrogenic,
or progestational effects.
[0116] Progesterone is metabolically converted to the GABA.sub.A
receptor-potentiating neuroactive steroid allopregnanolone by
5.alpha.-reductase isoenzymes followed by 3.alpha.-hydroxysteroid
oxidoreduction. Finasteride acts as a competitive
5.alpha.-reductase inhibitor and thus blocks the production of
allopregnanolone from progesterone.
[0117] In one embodiment, finasteride is delivered using at least
one oral tablet with a total daily dose of less than 10 mg,
preferably less than 5 mg. It should be appreciated that, to the
extent approved by regulatory authorities, finasteride can also be
delivered in gel capsules or via injection or infusion. Finasteride
should not be used by women of childbearing age. Finasteride's side
effects include breast enlargement and tenderness, skin rash,
swelling of lips, abdominal pain, back pain, decreased libido,
decreased volume of ejaculate, diarrhea, dizziness, headache,
impotence, and testicular pain.
[0118] 2. Dutasteride
[0119] Dutasteride is a synthetic 4-azasteroid compound that is a
selective inhibitor of both the Type I and Type II isoforms of the
steroid 5.alpha.-reductase, an intracellular enzyme. Dutasteride is
chemically designated as (5.alpha.,17.beta.)-N-{2,5
bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide.
The empirical formula of dutasteride is
C.sub.27H.sub.30F.sub.6N.sub.2O.sub.2, representing a molecular
weight of 528.5.
[0120] As a competitive Type I and Type II 5.alpha.-reductase
inhibitor, dutasteride inhibits the conversion of progesterone to
allopregnanolone. Dutasteride does not bind to the human androgen
receptor.
[0121] In one embodiment, dutasteride is delivered using at least
one capsule with a total daily dose of less than 10 mg, preferably
less than 0.5 mg. It should be appreciated that, to the extent
approved by regulatory authorities, dutasteride can also be
delivered in tablets or via injection or infusion. Dutasteride
should not be used by women of childbearing age. Dutasteride's side
effects include cough, difficulty swallowing, dizziness, fast
heartbeat, hives or welts, itching skin, puffiness or swelling of
the eyelids or around the eyes, face, lips, or tongue, redness of
skin, shortness of breath, skin rash, swelling of face, fingers,
feet, and/or lower legs, tightness in chest, unusual tiredness or
weakness, wheezing, abnormal ejaculation, decreased interest in
sexual intercourse, decreased sexual performance or desire,
impotence, inability to have or keep an erection, loss in sexual
ability, desire, drive, or performance, or swelling of the breasts
or breast soreness.
[0122] 3. Other 5.alpha.-Reductase Inhibitors
[0123] The present invention also encompasses the use of other
5-alpha reductase inhibitors, including a) 4-aza-4-methyl-5
alpha-pregnane-3,20-dione (AMPD), which inhibits pituitary
progesterone 5-alpha reduction, b) cyproterone acetate, and c)
spironolactone, which is a diuretic that blocks two pathways to the
production of androgens, or male hormones, one of which is the
inhibition of 5.alpha.-reductase.
[0124] The present invention also encompasses the use of organic
sources of 5-alpha reductase inhibition, including organic sources
such as saw palmetto. Saw palmetto (Serenoa repens) is a natural
source of a 5.alpha.-reductase inhibitor. Some studies suggest that
it may be comparable to finasteride if taken for six months. Saw
Palmetto is advantageous because it is 1) substantially free of
side effects and 2) cost effective.
[0125] ii. Other Inhibitors of Neurosteroid Production
[0126] The present invention further includes the use of
3.alpha.-hydroxysteroid oxidoreductase blockers. Gallo and Smith
(1993) suggest that the anxiogenic withdrawal property of
progesterone could be prevented by previous administration of a
3.alpha.-hydroxysteroid oxidoreductase blocker. In one embodiment,
indomethacin is used. Indomethacin is a non-steroidal
anti-inflammatory drug (NSAID) that reduces fever, pain and
inflammation. It is similar to ibuprofen and naproxen. Indomethacin
is effective in reducing the production of prostaglandins.
[0127] It should be appreciated that any composition that can be
used to inhibit neurosteroid production can be used in the present
invention. In one embodiment, compounds are preferably screened to
determine whether they can be used in the treatment methodologies
of the present invention.
[0128] Specifically, an appropriate cellular model is used to model
the inhibition of neurosteroid production. The efficacy of the
composition is measured by measuring the relative levels of
progesterone and allopregnanolone in a model prior to the
administration of the composition and after the administration of
the composition. In cases where the relative levels of progesterone
and allopregnanolone decrease after administration, the composition
may be suitable as an inhibitor to neurosteroid production.
[0129] b. Compounds that Modulate the Expression of Certain
GABA.sub.A Receptor Subunits
[0130] Molecular biology studies have revealed a high degree of
structural heterogeneity of the GABA.sub.A receptors. Development
of subtype selective or specific compounds is of key importance for
the understanding of the physiological and pathological roles of
different GABA receptor subtypes and may lead to valuable
therapeutic agents. It has been shown that functional selectivity
is obtainable for a number of GABA.sub.A agonists.
[0131] Characterizations of the role of GABA.sub.A receptors
require an understanding of the mechanisms by which subunit
composition is regulated. The long-term administration of
sedative-hypnotic, anxiolytic, or anticonvulsant drugs can affect
expression of GABA.sub.A receptor subunit genes as well as the drug
sensitivity and function of these receptors, suggesting that the
mechanisms responsible for such changes might also underlie the
physiological modulation of GABA.sub.A receptors by endogenous
compounds such as neurosteroids.
[0132] The level of efficacy of a partial agonist/antagonist
depends upon the disease or dependence in question. Thus, by
measuring the level of efficacy or activity of a partial
agonist/antagonist at a receptor site, it is possible to determine
what the disease state is and determine what conformational changes
have occurred in the GABA.sub.A receptor subunits. Based upon this
information, certain compositions can be classified according to
the changes they cause in GABA.sub.A subunits. In addition, since
the GABA binding site in the GABA.sub.A receptor is located at the
interface between .alpha. and .beta. subunits, the GABA.sub.A
antagonists can bind to and stabilize a distinct inactive receptor
conformation.
[0133] The present invention is thus directed towards a class of
compounds that modulates the expression of certain GABA.sub.A
receptor subunits. More specifically, the compound is one that
serves as an agonist at the GABA.sub.A receptor, and more
specifically, at either the .alpha..sub.4 subunit or .alpha..sub.6
subunit, and is capable of positively potentiating GABA
current.
[0134] Still more specifically, the compound of choice is one that
a) acts a partial agonist of GABA.sub.A; b) inhibits the
up-regulation of the .alpha..sub.4 subunit and/or increases the
amount of the .alpha..sub.1 subunit relative to the amount of the
.alpha..sub.4 subunit; and c) does not cause the up-regulation of
the .alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the al
subunit once the compound is no longer present in the patient's
system.
[0135] The changes in expression of the GABA.sub.A receptor
.alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit can be attributed to many factors. These
include, but are not limited to 1) compositions, both endogenous
and exogenous, that transform the GABA.sub.A receptor .alpha..sub.4
subunit relative to the GABA.sub.A receptor .alpha..sub.1 subunit
and vice versa; 2) compositions that result in the decrease of
expression of the GABA.sub.A receptor .alpha..sub.4 subunit or the
increase of expression of the GABA.sub.A receptor .alpha..sub.1
subunit; and 3) compositions that do not modify existing subunit
levels, but rather prevent the upregulation of GABA.sub.A receptor
.alpha..sub.4 subunit.
[0136] Thus, the compound of choice is one that effectuates an
increase in the expression of the GABA.sub.A receptor .alpha..sub.1
subunit relative to the expression of the .alpha..sub.4 subunit.
This increase in expression of the .alpha..sub.1 subunit may be
effectuated by one or more of the following: a) upregulating the
expression of .alpha..sub.1 subunits; b) downregulating the
expression of .alpha..sub.4 subunits; c) masking .alpha..sub.4
subunits; or d) preventing the upregulation of the .alpha..sub.4
subunit.
[0137] The focus is thus on using a compound from the class of
compounds that modulates the expression of certain GABA.sub.A
receptor subunits, and more specifically, moves the relative
balance of the .alpha..sub.4 subunit to the .alpha..sub.1 subunit
closer to a normal state from an abnormal, allostatic state.
[0138] i. Flumazenil
[0139] In one embodiment, the present invention relates to the use
of a therapeutically effective quantity of a drug, and more
specifically, one that modulates the expression of GABA.sub.A
subunits, such as, but not limited to, flumazenil, in a methodology
for treatment of substance abuse. In one embodiment, the compound
may comprise certain imidazobenzodiazepines and derivatives of
ethyl
8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-
-3-carboxylate, including various substitutions of the carboxylate
functional group, such as carboxylic acids, esters, acyl chlorides,
acid anhydrides, amides, nitriles, alkyls, alkanes, cycloalkanes,
alkenes, alcohols, aldehydes, ketones, benzenes, phenyls, and salts
thereof. In another embodiment, the compound comprises flumazenil
or carboxylic acids, esters, acyl chlorides, acid anhydrides,
amides, nitriles, alkyls, alkanes, cycloalkanes, alkenes, alcohols,
aldehydes, ketones, benzenes, phenyls, and salts thereof.
[0140] Flumazenil acts a partial agonist of GABA.sub.A, inhibits
the upregulation of the .alpha..sub.4 subunit and/or increases the
amount of the .alpha..sub.1 subunit relative to the amount of the
.alpha..sub.4 subunit, and does not cause the upregulation of the
.alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the
.alpha..sub.1 subunit once the compound is no longer present in the
patient's system.
[0141] ii. Miltirone
[0142] In another embodiment, the compound may comprise miltirone,
as described in Mostallino et al., "Inhibition by miltirone of
up-regulation of GABA.sub.A receptor .alpha..sub.4 subunit mRNA by
ethanol withdrawal in hippocampal neurons", European Journal of
Pharmacology, 494 (2004) 83-90.
[0143] iii. Flavonoids
[0144] In another embodiment, the compound may comprise certain
flavonoids that act as a partial agonist of GABA.sub.A, inhibit the
upregulation of the .alpha..sub.4 subunit and/or increase the
amount of the .alpha..sub.1 subunit relative to the amount of the
.alpha..sub.4 subunit, and does not cause the upregulation of the
.alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the al
subunit once the compound is no longer present in the patient's
system.
[0145] It should be appreciated that any composition that can
function as described above, can be used in the present invention.
In one embodiment, compounds are preferably screened to determine
whether they can be used in the treatment methodologies of the
present invention. In one embodiment, experiments are conducted to
determine whether it functions as a partial agonist of GABA.sub.A,
inhibits the upregulation of the .alpha..sub.4 subunit, and does
not cause the upregulation of the .alpha..sub.4 subunit once the
compound is no longer present in the patient's system. While one of
ordinary skill in the art can devise such experiments, an exemplary
embodiment of such an experiment is provided in Mostallino et al.,
"Inhibition by miltirone of up-regulation of GABA.sub.A receptor
.alpha..sub.4 subunit mRNA by ethanol withdrawal in hippocampal
neurons", European Journal of Pharmacology, 494 (2004) 83-90.
VI. Novel Treatment Methodologies
[0146] The present invention is directed towards a comprehensive
treatment protocol that employs methods of, and compositions for,
preparing a patient for treatment and modulating the expression of
certain GABA.sub.A receptor subunits. The present invention
therefore treats symptoms associated with physiological tolerance
to and withdrawal from certain steroids, and in particular
endogenous neurosteroids, in the context of a comprehensive
treatment plan of behavioral and/or pharmacological treatment.
[0147] More specifically, the present invention relates to methods
of, devices for, and treatment protocols for using pharmaceutical
compositions from a class of compounds that modulates GABA.sub.A by
modulating the expression of the GABA.sub.A receptor .alpha..sub.4
subunit relative to the GABA.sub.A receptor .alpha..sub.1 subunit.
The treatment of choice is one that resets the compositional
profile of the GABA receptor, and more specifically, the GABA.sub.A
subunits, into a normal or a pre-tolerance state.
[0148] The multiple phase treatment methodology of the present
invention employs one or more compounds to reset physiochemical
changes, and thus alleviate a disease state, that are caused by the
brain's unconscious drive to alleviate anxiety arising from the
dysregulation of endogenous neurosteroids.
[0149] In one embodiment, the present invention is directed towards
treating indications that arise from the drive to address an
endogenous neurosteroid "withdrawal". Specifically, anxiety-related
disorders such as generalized anxiety disorder; panic disorder;
specific and social phobias; obsessive compulsive disorder;
post-traumatic stress disorder; and eating disorders, including
anorexia nervosa, bulimia nervosa, and binge eating disorder, have,
as part of their cause, a biologically detrimental physiological
and psychological response to addressing anxiety brought on by
endogenous neurosteroid withdrawal.
[0150] Effective treatment of such indications requires addressing
the maladaptive behaviors underlying psychological and
physiological tolerance to and withdrawal from various endogenous
neurosteroids, namely the increased expression of the GABA.sub.A
receptor .alpha..sub.4 subunit relative to the .alpha..sub.1
subunit.
[0151] The treatment methodology of the present invention thus
incorporates 1) determining if a person is in a receptive state for
treatment and/or causing a person to be in a receptive state for
treatment and 2) treating a person using appropriate drugs in a
comprehensive treatment protocol that includes pre-drug assessment
including optional detoxification, treatment, and aftercare. The
term "receptive state", as used herein, refers to a physiological
state in which the patient is withdrawn from both endogenous and
exogenous substances.
[0152] As used in this description, the term patient refers to a
male or female human being of any race, national origin, age,
physiological make-up, genetic make-up, disease predisposition,
height, or weight, and having any disease state, symptom or
illness.
[0153] It should further be appreciated that the methods and
processes of the present invention can be implemented in a computer
system having a data repository to receive and store patient data,
a memory to store the protocol steps that comprise the methods and
processes of the present invention, a processor to evaluate patient
data in relation to said protocol steps, a network interface to
communicate via a network with other computing devices and a
display to deliver information to users. In one embodiment,
specific protocol steps are stored in said memory and compared
against patient data, including behavioral, psychological or
physiological profiles, to determine which protocol steps should be
applied. Results of the comparison are communicated to a user via a
network and other computing devices or display. The methodologies
of the present invention are therefore accessed, tailored, and
communicated as a software program operating on any hardware
platform.
[0154] The exemplary treatment methodology of the present invention
comprises pre-treatment, co-treatment, and post-treatment phases
further comprising various components of an exemplary methodology.
As described herein, reference will be made to specific components
of the individual phases of the treatment methodology. It should be
noted, however, that the individual components comprising each
phase of the methodology--pre-treatment, co-treatment, and
post-treatment--are interchangeable and may be performed variably,
and should be determined on a per-patient basis. Thus, any
reference to administering the individual components of the phases
of methodology in a particular order is exemplary and it should be
understood to one of ordinary skill in the art that the
administration of methodology may vary depending on the assessed
needs of the patient. Furthermore, while the invention will be
described in conjunction with specific embodiments, it is not
intended to limit the invention to one embodiment. In addition,
many combinations of the methodology components described above are
possible; thus, the invention is not limited to such examples as
provided.
[0155] a. Pre-Treatment/Patient Assessment Phase
[0156] Prior to admittance into the treatment program of the
present invention, each patient should undergo a pre-treatment
analysis. The pre-treatment analysis may be used to determine
whether a patient is a candidate for the treatment methodology of
the present invention. In addition, the pre-treatment process may
be administered to prepare a patient for admittance into the
treatment methodology of the present invention. The pre-treatment
phase typically includes, but is not limited to a medical history
and physical examination, a psychological and behavioral
assessment, a determination of required medications, and
detoxification if needed to render the patient in a state receptive
to treatment.
[0157] The treatment methodology for anxiety-related disorders and
disease states has multiple phases and components that, in
combination, provide a comprehensive and integrated neurological,
physiological, and psychosocial approach for the diagnosed patient.
Each component has been selected to address specific criteria for
anxiety-related disorders and disease states and the corresponding
symptoms of endogenous neurosteroid withdrawal, with the objective
of restoring a balance in neurological circuits.
[0158] The methodology does not address a treatment protocol for a
patient in immediate danger of harm to oneself or others, or a
patient experiencing an anxiety-related symptom that requires
emergency attention, which may be associated with an
anxiety-related disorder or disease state. It is, therefore,
essential that each patient be assessed and the appropriate
treatments be instituted to address immediate patient need, with
due consideration for the potential interaction of any medicaments
used for this treatment with those used for the immediate emergency
treatment.
[0159] While the present methodology can be applied to any patient,
it is preferred that the patient be equal to or greater than
eighteen years old.
[0160] i. Complete Physical Examination
[0161] Before starting the treatment, the patient undergoes a
medical history, physical examination and laboratory assessment,
including but not limited to a complete blood count, a biochemical
profile [for example, creatinine, glucose, urea, cholesterol (HDL
and LDL), triglycerides, alkaline phosphatase, LDH (lactic
dehydrogenase) and total proteins], hepatic function tests [GOT,
GPT, GGT, bilirubin), electrocardiogram and, if appropriate,
pregnancy test and x-ray examinations. Exclusion criteria are
applied to ensure no other acute or uncompensated illness exists
within the patient and to ensure that the patient does not require,
or is currently not taking, a drug that is contraindicated with the
GABA.sub.A receptor modulating compound being used.
[0162] It should further be noted that certain exclusion criteria
should be applied to the screening of patients. The exclusion
criteria may be tailored to an outpatient or inpatient treatment
scenario. For example, it is preferred not to treat a patient on an
inpatient basis for an anxiety-related disorder where the where the
patient has current medical or psychiatric problems that, per the
screening physician, require immediate professional evaluation and
treatment, has current medical or psychiatric problems that, per
the screening physician, render the client unable to work
successfully with the methodology or with the staff administering
the treatment, or has current benzodiazepine and other
sedative-hypnotic-anxiolytic use (urine toxicology must be
negative).
[0163] If a patient is currently under pharmacological treatment
for the anxiety-related disorder, as described in greater detail
below, the patient should be safely weaned off of the medication
under the supervision of the treating physician.
[0164] ii. Diagnosis of Anxiety-Related Disorder
[0165] It is preferred that the patient meet at least a portion of
recognized criteria for anxiety-related and mental disorders, such
the in the Diagnostic and Statistical Manual of Mental Disorders
4th edition (DSM-IV). For example, DSM-IV criteria state that
anxiety disorders include not only generalized anxiety disorder
(GAD), social anxiety disorder (SAD, also known as social phobia),
specific phobia and panic disorder (PD), with and without
agoraphobia, but also obsessive-compulsive disorder (OCD) and
post-traumatic stress disorder (PTSD). While the DSM-IV criteria
are known to those of ordinary skill in the art, they are outlined
below with respect to the example treatment protocols below.
[0166] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention (Receptive State for Treatment)
[0167] It should be noted that the individual components comprising
the preparation phase of the methodology are interchangeable and
may be performed variably, and should be adapted to the patient.
Thus, any reference to administering the individual components of
the preparation phase of the methodology in a particular order is
exemplary and it should be understood to one of ordinary skill in
the art that the administration of methodology may vary depending
on the assessed needs of the patient. In addition, many
combinations of the methodology components described above are
possible; thus, the invention is not limited to such examples as
provided.
[0168] i. Assessing Patient's Current Treatment/Industry-Standard
Treatment Approaches
[0169] In one embodiment, a patient with an anxiety disorder may
already be in the process of treatment with a conventional
treatment methodology, including, but not limited to the use of
selective serotonin reuptake inhibitors. In another embodiment, the
patient may be "pre-treated" with standard and/or industry-accepted
treatment protocols. If a patient is currently undergoing
conventional treatment for the anxiety disorder with which he is
diagnosed, the patient is preferably weaned off of the medication
at least two to four weeks prior to beginning treatment with the
protocol of the present invention. Preferably, before beginning
treatment, the amount of the drug remaining in the patient is
substantially small. Thus, it is important to consider the
elimination half-life of the medication that the patient is
currently taking. With some medications, such as SSRI's, even when
dosing is stopped, active drug substance will persist in the body
for weeks (primarily depending on individual patient
characteristics, previous dosing regimen, and length of previous
therapy at discontinuation). It is important that these factors are
considered when preparing the patient for the treatment protocol of
the present invention.
[0170] Several exemplary treatment protocols are briefly described
in the sections below. It should be noted, however, that the
treatment protocols outlined herein are exemplary and any number of
treatment protocols may be used with the present invention provided
that they are not contraindicated with the use of any of the
pharmacological compounds for use with the treatment protocol of
the present invention, including but not limited to a compound from
the class of compounds that increases the relative expression of
the .alpha..sub.1 GABA.sub.A subunit relative to the .alpha..sub.4
GABA.sub.A subunit and inhibitors of neurosteroid production.
[0171] It should also be noted that the pharmacological compounds
described with respect to the conventional treatment protocols
should be used according to published FDA dosage guidelines, which
are herein incorporated by reference. While dosing parameters are
not described in detail below with respect to the example treatment
protocols, Table 1 offers some exemplary treatment parameters for
many of the pharmacological compounds described herein, and is
herein incorporated by reference.
[0172] Many of the conventional protocols described herein are
adapted by the National Guideline Clearinghouse. The National
Guideline Clearinghouse.TM. (NGC) is a comprehensive database of
evidence-based clinical practice guidelines and related documents.
NGC is an initiative of the Agency for Healthcare Research and
Quality (AHRQ), U.S. Department of Health and Human Services. NGC
was originally created by AHRQ in partnership with the Americal
Medical Association and the American Association of Health Plans
(now America's Health Insurance Plans [AHIP]). The NGC mission is
to provide physicians, nurses, and other health professionals,
health care providers, health plans, integrated delivery systems,
purchasers and others an accessible mechanism for obtaining
objective, detailed information on clinical practice guidelines and
to further their dissemination, implementation and use.
[0173] Certain clinical practice guidelines were also adapted from
the Expert Consensus Guidelines are being used throughout the
country by clinicians, policy-makers, administrators, case
managers, mental health educators, patient advocates, and clinical
and health services researchers.
[0174] As mentioned above, the use of industry-accepted treatment
protocols is optional.
[0175] ii. Placing a Patient in a State of Withdrawal
[0176] After a patient is diagnosed and optionally treated with a
conventional treatment protocol for treating an anxiety disorder,
the patient is placed in a state of withdrawal. As used herein, the
term "withdrawal" refers to a physiological state in which an
individual has begun to have adverse psychological and/or
physiological effects from not having a bioavailable amount of
particular substance or from having a decreasing bioavailable
amount of a particular substance. In one embodiment, the particular
substance is an endogenous neurosteroid. In another embodiment, the
particular substance is allopregnanolone. More specifically,
withdrawal can be attributed to an increase in the GABA.sub.A
receptor .alpha..sub.4 subunit expression relative to the
GABA.sub.A receptor .alpha..sub.1 subunit.
[0177] The treatment methodologies of the present invention include
a first step of placing a patient in a state of withdrawal. In one
embodiment, a person is placed in a receptive state for treatment
by actively inhibiting the upregulation of endogenous neurosteroids
and/or causing the downregulation of endogenous neurosteroids. The
upregulation of neurosteroids could be caused by a number of
external factors, including the ingestion or administration of
certain substances, such as caffeine or nicotine, or psychological
stress. The present invention therefore includes the step of
avoiding all such activities that could result in the upregulation
of an individual's neurosteroid level.
[0178] In another embodiment, a person is placed in a receptive
state for treatment by actively causing the downregulation of
endogenous neurosteroids, such as allopregnanolone, through the
administration of inhibitors of neurosteroid production that block
the production of endogenous neurosteroids and/or their
metabolites. The present invention also includes the inhibition of
the modulatory effects of neurosteroids on GABA.sub.A. By doing so,
one accelerates the exposure or upregulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits and ensures that a
substantial number of .alpha..sub.4 subunits are exposed and
available to enhance the efficacy of subsequent treatment
steps.
[0179] The present invention further includes the step of actively
causing the downregulation of endogenous neurosteroids, such as
allopregnanolone, through the administration of agents that block
the production of endogenous neurosteroids and/or their
metabolites. The present invention also includes the inhibition of
the modulatory effects of neurosteroids on GABA.sub.A. By doing so,
one accelerates the exposure or upregulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits and ensures that a
substantial number of undesirable subunits are exposed and
available for enhanced pharmacotherapeutic efficacy.
[0180] Particular methods for baselining endogenous neurosteroid
production to a consistent level in the pre-treatment portion of
the protocol are discussed below, but the treatment protocol is not
limited to such methods. For the methods listed below, the present
invention contemplates operating in a dosing range of established
safety and efficacy in order to maximally decrease the production
of progesterone and make the individual most receptive to
treatment.
[0181] 1. Avoid Stress-Inducing Activities
[0182] In one embodiment, the present invention includes the step
of avoiding all such activities that could result in the
upregulation of an individual's neurosteroid level and the step of
actively causing the downregulation of endogenous neurosteroids,
such as allopregnanolone. It should be noted that stress-inducing
activities depend upon the patient and the patient's general
condition. Thus, individual recommendations may be made by the
treating physician.
[0183] 2. Avoid Neurosteroid Production Enhancing Activities
[0184] The patient is advised to not engage in activities, or
ingest any substances, that could likely increase neurosteroid
production. Such activities include sex, stressful activities,
fighting, or intense arguing. Such substances include chocolate,
illegal drugs, prescription drugs, or over the counter
medicines.
[0185] Although not preferred because these compositions may serve
to increase neurosteroid production, in certain cases, it may be
necessary to administer a composition to reduce stress.
[0186] In one embodiment, the stress-reducing composition is
gabapentin. Gabapentin is an anxiolytic and anticonvulsant
medication typically prescribed to patients suffering from epilepsy
(effectively lowers brain glutamate concentrations) and has also
been used in the treatment of anxiety disorders such as social
anxiety disorder and obsessive-compulsive disorder. Prior to
administering gabapentin to a patient, it is essential to assess
the patient for interactions and contraindications. Gabapentin is
to be used in adjunctive therapy in the treatment of epilepsy
seizures (partial) and for the management of postherpetic
neuralgia. Gabapentin is not appreciably metabolized and is
excreted unchanged with an elimination half-life of 5-7 hours.
Possible side effects from the use of gabapentin are dizziness,
somnolence, other symptoms/signs of CNS depression, nausea, ataxia,
tremor, and peripheral edema. In persons with epilepsy, abrupt
discontinuation may increase seizure frequency. No clinically
significant drug interactions have been reported in the
literature.
[0187] In another embodiment, the stress-reducing composition is a
H1 histamine receptor agonist, such as, but not limited to
hydroxyzine. Hydroxyzine is indicated for treatment of generalized
anxiety disorder symptoms and for use in the management of
withdrawal from substance dependence during both the initial phase
of inpatient treatment and post-discharge care (as necessary). It
also has anti-emetic and skeletal muscle relaxation benefits and
can be used as a sedative. This sedative effect can be useful for
treating the sleep-disordered breathing and increased periodic leg
movements that contribute to the insomnia often seen in patients
recovering from alcohol dependency. This helps address on-going
insomnia which, for some patients is significantly associated with
subsequent alcoholic relapse.
[0188] Hydroxyzine is rapidly absorbed and yields effects within
15-30 minutes after oral administration. In addition, hydroxyzine
aids the substance withdrawal process through anxiolytic,
anti-nausea, relaxant, and various other properties. It should be
noted that the effects of other sedating or tranquilizing agents
may be synergistically enhanced with the administration of
hydroxyzine. Exemplary trade names of these drugs include Atarax
and Vistaril.
[0189] 3. Avoid Heightened Progesterone Levels In Patient
[0190] In an optional embodiment, it is possible to minimize
endogenous neurosteroid production by timing the treatment in a
manner that avoids heightened progesterone cycles.
[0191] In women, progesterone levels are low during the
pre-ovulatory phase of the menstrual cycle, rise after ovulation,
and are elevated during the luteal phase. Specifically,
progesterone levels tend to be <2 ng/ml prior to ovulation, and
>5 ng/ml after ovulation. If pregnancy occurs, progesterone
levels are maintained at luteal levels initially. With the onset of
the luteal-placental shift in support of the pregnancy,
progesterone levels start to rise further and may reach 100-200
ng/ml at term. After delivery of the placenta and during lactation,
progesterone levels are low.
[0192] For example, but not limited to such example, since
progesterone levels are highest during the luteal phase of the
menstrual cycle, it is preferred not to treat a woman during this
time window. Conversely, it is preferred to treat a woman during
the pre-ovulatory phase of the menstrual cycle, when progesterone
levels are low.
[0193] Progesterone levels are low in children, men, and
postmenopausal women.
[0194] 4. Actively Modulate a Woman's Progesterone Levels
[0195] In another embodiment, a woman's progesterone is actively
modulated by the administration of prescription hormones, such as,
but not limited to, contraception with progesterone, that keeps the
woman on a constant progesterone level. Such contraception includes
progestin implants and levonorgestrel implants. Administration of
these compositions will effectively make a woman's progesterone
levels constant.
[0196] Upon withdrawal of these contraception compositions, the
woman's hormone level will decrease, thereby "unmasking" its
.alpha..sub.4 receptor subunits and placing a woman in a state most
receptive to treatment.
[0197] The present invention advantageously uses the time gap
between when administered progesterone leaves the system and when
endogenous progesterone production resumes. In one embodiment, this
minimal progesterone point window is preferably when the treatment
protocol of the present invention should begin.
[0198] In one embodiment, progesterone can be delivered orally,
sublingually, via vaginal suppositories, via injection, topically,
transdermally, or by implant. The rate of absorption of
progesterone is highly dependent upon the administration route.
Irrespective of the type used, progesterone, progestin, or other
progesterone-like compounds should be administered in sufficient
amounts to attain a heightened level of progesterone and then
terminated in sufficient time to allow for the progesterone levels
to decrease prior to treatment.
[0199] It should again be noted that Table 1 offers an exemplary
listing of pharmacological compounds in the classes of compounds
described herein. Several examples of contraception and recommended
dosing parameters are also listed in Table 1.
[0200] 5. Actively Modulate a Male's or Female's Progesterone
Cycle
[0201] As mentioned above, various neurosteroid inhibitors prevent
the conversion of progesterone into allopregnanolone. In an
endogenous case, allopregnanolone is responsible for the modulation
of the GABA.sub.A receptors. By compensating for the effects of
anxiety and anxiety-related symptoms, endogenous neurosteroids,
when elevated, "mask" GABA.sub.A receptors and prevent flumazenil
from being able to "re-set" those receptors. The administration of
these drugs can effectively drive down endogenous neurosteroid
levels.
[0202] In one embodiment, the compound is a 5.alpha.-reductase
inhibitor. Preferably, the 5.alpha.-reductase inhibitor is capable
of acting as a Type I inhibitor, a Type II inhibitor or a
combination thereof and inhibits the 5.alpha.-reductase enzyme from
converting progesterone to 5.alpha.-dihydroprogesterone and thus
from creating progesterone metabolite allopregnanolone. In another
embodiment, the compound is a 3.alpha.-hydroxysteroid
oxidoreductase inhibitor, which prevents the
3.alpha.-hydroxysteroid oxidoreductase enzyme from converting
5.alpha.-dihydroprogesterone into 5.alpha.,3.alpha.-pregnanolone
(allopregnanolone).
[0203] While the class of compounds that inhibit neurosteroid
production has been described in detail above, an exemplary list of
compounds is described in detail in Table 1. It should be noted,
however, that the present invention is not limited to such
compounds and any compounds that effectively inhibit endogenous
neurosteroid production, and in particular, the conversion of
progesterone to its metabolite allopregnanolone, can be used with
the present invention.
[0204] c. Administration of a Compound from the Class of Compounds
that Modulates the Expression of Certain GABA.sub.A Receptor
Subunits
[0205] Whether used independently of, or part of, any other
treatment approach, the present invention requires a patient to be
administered a compound from the class of compounds that modulates
the expression of certain GABA.sub.A receptor subunits, as
described above. In one embodiment, the compound serves as an
agonist at the GABA.sub.A receptor, and more specifically, at
either the .alpha..sub.4 subunit or .alpha..sub.6 subunit, and is
capable of positively potentiating GABA current.
[0206] It should be noted, however, that the present invention is
not limited to such compounds and any compounds that effectively
increase the expression of the .alpha..sub.1 GABA.sub.A subunit
relative to the .alpha..sub.4 GABA.sub.A subunit, in a
non-transitory manner, can be used with the present invention.
[0207] The present invention is directed towards, in one
embodiment, the use of a compound that modulates the expression of
certain GABA.sub.A receptor subunits, such as flumazenil, in
multiple doses for a predetermined time period as part of the
treatment methodology. When administered in accordance with the
present invention, a therapeutically effective amount of the drug
is maintained in the patient, thereby significantly reducing the
upregulation of allopregnanolone. The methodology of the present
invention also provides for the administration of a compound that
modulates the expression of certain GABA.sub.A receptor subunits,
such as flumazenil, without significant side effects.
[0208] Thus, in one embodiment, a method is provided for the
treatment of anxiety-related disorders and disease states that
includes the administration to a patient in need of said treatment
of a therapeutically effective quantity of flumazenil in multiple
doses during predetermined time periods/intervals, until a
therapeutically effective quantity of flumazenil to treat
anxiety-related disease states has been reached, as measured by
quantitative and/or qualitative assessments of, for example, a
patient's blood pressure, heart rate, and feelings of anxiety.
Thus, it is possible to administer flumazenil in variable doses to
obtain the desired therapeutic response, reducing the risk of
secondary effects in the patient (as a result of reducing the
quantity of drug administered per dose applied).
[0209] In another embodiment, a method is provided for the
treatment of anxiety-related disorders and disease states that
includes the administration to a patient in need of said treatment
of a therapeutically effective quantity of flumazenil, usually
between 0.5 mg/day and 20 mg/day, between 0.5 mg/day and 15 mg/day,
specifically between 1.0 and 3.0 mg/day, and more specifically
between 1.5 and 2.5 mg/day, of flumazenil, broken down into
multiple doses of flumazenil between 0.1 and 0.3 mg and intended
for administration during predetermined time periods or intervals,
until said therapeutically effective quantity of flumazenil to
treat the disorder has been reached. In one embodiment, the
predetermined time period is in the range of 1 and 15 minutes and
the "per dose" quantity of flumazenil is between 0.1 and 0.3
mg.
[0210] One of ordinary skill in the art would appreciate that the
individual doses can range in amount, and the time interval between
the individual doses can range in amount, provided that the total
dose delivered is in the range of 1.0 mg/day and 3.0 mg/day and the
individual doses are delivered at relatively consistent time
intervals. Therefore, the time period intervals can range from 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, or 25 minutes or fractions thereof. Doses delivered
at each time period, separated by the time intervals, can be
between 0.1 and 0.3 mg, or fractions thereof, keeping in mind the
total drug delivered is preferably less than 3.0 mg/day. The
present invention therefore provides for the delivery of multiple,
sequential doses, delivered at substantially consistent time
intervals.
[0211] Conventional uses of flumazenil comprise either singular
doses or much larger doses over shorter periods of time and are
directed toward reversing sedative effects of anesthesia, conscious
sedation, or benzodiazepine overdose. Further, Romazicon, a brand
name for flumazenil marketed by Roche, is expressly indicated to
complicate the management of withdrawal syndromes for alcohol,
barbiturates and cross-tolerant sedatives and was shown to have an
adverse effect on the nervous system, causing increased agitation
and anxiety. For a single dose to address anesthesia and conscious
sedation, it is conventionally recommended to use a dose of 0.2 mg
to 1 mg of Romazicon with a subsequent dose in no less than 20
minutes. For repeat treatment, 1 mg doses may be delivered over
five minutes up to 3 mg doses over 15 minutes. In benzodiazepine
overdose situations, a larger dose may be administered over short
periods of time, such as 3 mg doses administered within 6 minutes.
One of ordinary skill in the art would appreciate that such
conventional uses of flumazenil are not directed toward the
treatment of substance abuse.
[0212] In addition, the administration method of the present
invention provides a better use of flumazenil to treat the symptoms
of withdrawal and to reduce the unnecessary consumption of said
drug, thereby increasing convenience and the quality of life of the
patient and reducing cost by treating the patient in a very short
period of time.
[0213] The method for the treatment of anxiety-related disorders
and disease states provided by this invention is applicable to any
patient who, when the treatment is to begin, has no medical
illnesses that would make treatment with a compound that modulates
the expression of certain GABA.sub.A receptor subunits, such as
flumazenil hazardous or is taking medication contraindicated with a
compound that modulates the expression of certain GABA.sub.A
receptor subunits.
[0214] In one embodiment, a compound that modulates the expression
of certain GABA.sub.A receptor subunits, such as flumazenil, is
administered until qualitative and quantitative parameters
indicative of an anxiety-related disorder are lowered to acceptable
ranges.
[0215] In one embodiment, a compound that modulates the expression
of certain GABA.sub.A receptor subunits, such as flumazenil, is
administered at the latter of a) when the patient starts to feel
anxious (this is when receptors are "unmasked" as progesterone is
substantially no longer converted to allopregnanolone) or b) when
it is safe to administer based upon prior drugs given to the
patient.
[0216] In one embodiment, a compound that modulates the expression
of certain GABA.sub.A receptor subunits, such as flumazenil, is
administered at any rate, provided that the rate is not detrimental
to the patient, as determined by patient self-report of symptoms,
or physiological parameters such as heart rate, heart rhythm, or
blood pressure.
[0217] d. Additional Treatment Options
[0218] In some cases, in may be necessary to use, either during or
post-treatment, the following optional components of the treatment
protocol. The following optional components are exemplary and are
dependent upon a variety of factors, including but not limited to
responsiveness of the patient to treatment and if there is an
indication of a sustained increase in 5-alpha reductase
activity.
[0219] i. 5-Alpha Reductase Inhibitor
[0220] It may be necessary to continually treat a patient with a
5-alpha reductase inhibitor if there is an indication of a
sustained increase in 5-alpha reductase activity. 5-alpha-reductase
inhibitors have been described in detail above and will not be
repeated herein.
[0221] ii. Prolactin
[0222] In some cases, it may be necessary to treat a patient to
resolve increased production of prolactin, due to an increase of
estrogen levels caused by a decline in progesterone feedback. A
sustained increase in the levels of prolactin leads to impairment
of dopamine functionality, characterized by a higher stimulus
threshold for dopamine release. Exemplary drugs include dopamine
agonists, such as bromocriptine and prescription amphetamines, such
as Ritalin and Adderal.
[0223] e. Post-Treatment Phase of Protocol
[0224] After a patient successfully completes the treatment phase
of the methodology of the present invention, each patient will be
prescribed a post-treatment regimen to follow, which includes, but
is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. The components of the post-treatment phase of the
methodology of the present invention are described in greater
detail below.
[0225] Before discharge from the hospital, one or more of the
following compositions or drugs may be prescribed: gabapentin and
fluoxetine hydrochloride. Preferably, the compositions or drugs can
be administered in oral form to enable greater patient compliance
and convenience. It should be appreciated that, to the extent any
of drugs described herein are not available in the jurisdiction in
which this invention is being practiced equivalent functioning
drugs may be used.
[0226] Psychotherapy/behavioral therapy and counseling may be
critical for the success of anxiety-related and/or depressive
disorders and disease states when using pharmacological adjuncts.
Thus, the methodology also provides for a maintenance program that
includes medications and incentives for the patient to continue
with their treatment process through continuing care programs. Due
to the complexity of anxiety-related disorders and disease states,
patients benefit most from a combination of pharmacologic and
behavioral interventions.
[0227] As part of the treatment program, patients may optionally be
instructed to attend the outpatient treatment center for several
months with decreasing frequency [i.e., once a week for the first
three months, once every two weeks during the second three months,
and once a month during the third three months].
[0228] Likewise, a semi-structured follow-up of cognitive behavior
therapy is optionally implemented. Individual and family
psychotherapy is focused on a plurality of interventions, including
cognitive restructuring, work therapy, prevention of relapse, and
stress reduction, aimed at rehabilitating the social, family, work,
personal and leisure life of the patient.
[0229] Depending upon the results of the initial examination, a
universal or patient-specific diet plan may optionally be
administered in conjunction with the methodology. Depending upon
the results of the initial examination, a universal or
patient-specific exercise programs may optionally be administered
in conjunction with the methodology.
[0230] The following examples will serve to further illustrate the
present invention without, at the same time, however, constituting
any limitation thereof. On the contrary, it is to be clearly
understood that resort may be had to various embodiments,
modifications and equivalents thereof which, after reading the
description herein, may suggest themselves to those skilled in the
art without departing from the spirit of the invention.
VII. Example 1
Protocol for the Treatment of General Anxiety Disorder
[0231] Anxiety disorders are often debilitating and chronic
conditions that are exacerbated at high times of stress and may be
linked to changes in hormone levels in the body. In order to
compensate for these hormonal changes, or to increase progesterone
as described above, people tend to create more stress in their
lives. GABA-modulatory steroids, such as progesterone and its
metabolite allopregnanolone, affect GABA receptor functionality and
thus, when progesterone is down-regulated in an individual, such as
the case is with certain anxiety disorders, the expression of the
GABA.sub.A receptor .alpha..sub.4 subunit is increased relative to
the expression of the al subunit. By resetting GABA.sub.A to normal
levels of receptor subunits (decrease the amount of .alpha..sub.4
and increase the amount of .alpha..sub.1, which is more sensitive
to binding of GABA and benzodiazepines) it is possible to treat the
underlying disease state.
[0232] a. Pre-Treatment/Patient Assessment Phase
[0233] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0234] i. Diagnosis of General Anxiety Disorder
[0235] Generalized anxiety disorder is characterized, according to
DSM-IV criteria, by long-lasting anxiety that is not focused on any
particular object or situation. People with this disorder feel
afraid of something but are unable to articulate the specific fear.
Because of persistent muscle tension and automatic fear reactions,
they may develop headaches, heart palpitations, dizziness, and
insomnia. These physical complaints, combined with the intense,
long term anxiety, make it difficult to cope with normal daily
activities. Diagnostic criteria include: [0236] Excessive anxiety
and worry (apprehensive expectation), occurring more days than not,
for at least 6 months, about a number of events or activities (such
as work or school performance). [0237] The person finds it
difficult to control the worry. [0238] The anxiety and worry are
associated with three (or more) of the following six symptoms (with
at least some symptoms present for more days than not, for the past
6 months): restlessness or feeling keyed up or on edge; being
easily fatigued; difficulty concentrating or mind going blank;
irritability; muscle tension; sleep disturbance (difficulty falling
or staying asleep, or restless, unsatisfying sleep). [0239] The
focus of the anxiety and worry is not confined to features of an
Axis I disorder, e.g., the anxiety or worry is not about having a
panic attack (as in Panic Disorder), being embarrassed in public
(as in social phobia), being contaminated (as in
obsessive-compulsive disorder), being away from home or close
relatives (as in separation anxiety disorder), gaining weight (as
in anorexia nervosa), having multiple physical complaints (as in
somatization disorder), or having a serious illness (as in
hypochondriasis), and the anxiety and worry do not occur
exclusively during post-traumatic stress disorder. [0240] The
anxiety, worry or physical symptoms cause clinically significant
distress or impairment in social, occupational or other important
areas of functioning. [0241] The disturbance is not due to the
direct physiological effects of a substance (e.g., a drug of abuse,
a medication) or a general medical condition (e.g.,
hyperthyroidism) and does not occur exclusively during a mood
disorder, a psychotic disorder, or a Pervasive Developmental
Disorder.
[0242] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0243] i. Additional Pre-Treatments
[0244] If a patient is diagnosed and currently being treated with a
conventional treatment for the anxiety disorder, the patient will
need to be placed in a state of withdrawal, which includes, but is
not limited to, weaning the patient off of any pharmacotherapy
prescribed by the conventional treatment protocol. An exemplary
protocol is described below, and thus, it should be noted that the
invention is not limited to the use of such protocol.
[0245] "Clinical guidelines for the management of anxiety:
Management of Anxiety panic disorder, with or without agoraphobia,
and generalized anxiety disorder in adults in primary, secondary,
and community care." Published by the National Guideline
Clearinghouse, is herein incorporated by reference.
[0246] Traditional treatments for generalized anxiety disorder
include pharmacological treatment options, such as benzodiazepines
(such as diazepam, alprazolam, clonazepam, lorazepam, and
2-chlordesmethyldiazepam), buspirone, antidepressants (such as
extended release venlafaxine, paroxetine, fluvoxamine, and
citalopram) and certain tricyclics (such as imipramine and
clomipramine). In severe cases, antipsychotics may be used.
[0247] ii. Placing a Patient in a State of Withdrawal
[0248] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0249] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.A Receptor Expression
[0250] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0251] d. Additional Treatment Options
[0252] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0253] e. Post-Treatment Phase of Protocol
[0254] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0255] f. Hypothetical Treatment Example 1
[0256] Male, 30 years old, under DSM IV criteria, has been
diagnosed as having general anxiety disorder.
[0257] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0258] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0259] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0260] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0261] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0262] g. Hypothetical Treatment Example 2
[0263] Male, 30 years old, under DSM IV criteria, has been
diagnosed as having general anxiety disorder. He is currently under
pharmacotherapy, with medications including paroxetine, 20 mg/day
and alprazolam, 0.25 mg/day on an as needed basis (maximum 4 mg in
24 hours).
[0264] Patient Preparation Step 1: Six weeks prior to scheduled
treatment, patient is instructed to decrease paroxetine dosage 10
mg/day for two weeks. Four weeks prior to scheduled treatment,
patient is instructed to cease all medications, including
alprazolam and paroxetine.
[0265] Patient Preparation Step 2: Four weeks prior to scheduled
treatment, he is initiated on a scheduled finasteride
administration of 5 mg per day. Three days prior to scheduled
treatment, the finasteride administration is terminated and the
patient is instructed to not engage in any stress-inducing
activities or ingest any substances that would likely increase
neurosteroid production.
[0266] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0267] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0268] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0269] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
VIII. Example 2
Protocol for the Treatment of Panic Disorder
[0270] Panic disorder is characterized by brief attacks of intense
terror and apprehension that cause trembling and shaking,
dizziness, and difficulty breathing. Although panic attacks
sometimes seem to occur out of nowhere, they generally happen after
frightening experiences, prolonged stress, or even exercise.
[0271] a. Pre-Treatment/Patient Assessment Phase
[0272] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0273] i. Diagnosis of Panic Disorder
[0274] Diagnostic criteria include: A discrete period of intense
fear or discomfort, in which four (or more) of the following
symptoms develop abruptly and reach a peak within 10 minutes:
[0275] Both (1) and (2): [0276] (1) Recurrent unexpected panic
attacks [0277] (2) At least one of the attacks has been followed by
1 month (or more) of one or more of the following: [0278]
Persistent concern about having additional panic attacks [0279]
Worry about the implications of the attack or its consequences
[0280] A significant change in behavior related to the attacks
[0281] Presence or absence of agoraphobia [0282] The panic attacks
are not due to the direct physiological effects of a substance (eg,
a drug of abuse, a medication) or a general medical condition (eg,
hyperthyroidism). [0283] The panic attacks are not better accounted
for by another mental disorder.
[0284] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0285] i. Additional Pre-Treatments
[0286] If a patient is diagnosed and currently being treated with a
conventional treatment for the anxiety disorder, the patient will
need to be placed in a state of withdrawal, which includes, but is
not limited to, weaning the patient off of any pharmacotherapy
prescribed by the conventional treatment protocol. An exemplary
protocol is described below, and thus, it should be noted that the
invention is not limited to the use of such protocol.
[0287] "Clinical guidelines for the management of anxiety:
Management of Anxiety panic disorder, with or without agoraphobia,
and generalized anxiety disorder in adults in primary, secondary,
and community care." Published by the National Guideline
Clearinghouse, is herein incorporated by reference.
[0288] Traditional treatments for panic disorder include
pharmacological treatment options, such as buspirone,
antidepressants (such as extended release venlafaxine, paroxetine,
fluvoxamine, and citalopram) and certain tricyclics (such as
imipramine and clomipramine). In severe cases, antipsychotics may
be used.
[0289] ii. Placing a Patient in a State of Withdrawal
[0290] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-including activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0291] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.A Receptor Expression
[0292] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0293] d. Additional Treatment Options
[0294] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0295] e. Post-Treatment Phase of Protocol
[0296] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0297] f. Hypothetical Treatment Example 1
[0298] Male, 32 years old, under DSM IV criteria, has been
diagnosed as having panic disorder.
[0299] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0300] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0301] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0302] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0303] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0304] g. Hypothetical Treatment Example 2
[0305] Male, 32 years old, under DSM IV criteria, has been
diagnosed as having panic disorder. He is currently receiving
paroxetine, 40 mg/day.
[0306] Patient Preparation Step 1: Eight weeks prior to scheduled
treatment, patient is instructed to decrease paroxetine dosage to
20 mg/day for two weeks. Six weeks prior to scheduled treatment,
patient is instructed to further decrease paroxetine dosage to 10
mg/day for two weeks. Four weeks prior to scheduled treatment,
patient is instructed to cease all medications, including
paroxetine.
[0307] Patient Preparation Step 2: Four weeks prior to scheduled
treatment, he is initiated on a scheduled finasteride
administration of 5 mg per day. Three days prior to scheduled
treatment, the finasteride administration is terminated and the
patient is instructed to not engage in any stress-inducing
activities or ingest any substances that would likely increase
neurosteroid production.
[0308] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0309] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0310] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0311] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
IX. Example 3
Protocol for the Treatment of Specific Phobia and Social Phobia
Social Anxiety Disorder
[0312] A phobia is a strong, irrational fear and avoidance of an
object or situation. The person knows the fear is irrational, yet
the anxiety remains. Phobic disorders differ from generalized
anxiety disorders and panic disorders because there is a specific
stimulus or situation that elicits a strong fear response.
[0313] a. Pre-Treatment/Patient Assessment Phase
[0314] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0315] i. Diagnosis of Specific Phobia [0316] Marked and persistent
fear that is excessive or unreasonable, cued by the presence or
anticipation of a specific object or situation. [0317] Exposure to
the phobic stimulus almost invariably provokes an immediate anxiety
response, which may take the form of a situationally bound or
situationally predisposed panic attack. In children, the anxiety
may be expressed by crying, tantrums, freezing or clinging. [0318]
The person recognizes that the fear is excessive or unreasonable.
In children, this may be absent. [0319] The phobic situation (s) is
avoided or else is endured with intense anxiety or distress. [0320]
The avoidance, anxious anticipation, or distress in the feared
situation (s) interferes significantly with the person's normal
routine, occupational (or academic) functioning, or social
activities or relationships, or there is marked distress about
having the phobia. [0321] In individuals under 18 years, the
duration is at least 6 months. [0322] The anxiety, panic attacks,
or phobic avoidance associated with the specific object or
situation are not better accounted for by another mental
disorder.
[0323] ii. Diagnosis of Social Phobia (Social Anxiety Disorder)
[0324] A marked and persistent fear of one or more social or
performance situations in which the person is exposed to unfamiliar
people or to possible scrutiny by others. The individual fears that
he or she will act in a way (or show anxiety symptoms) that will be
humiliating or embarrassing. [0325] Exposure to the feared social
situation almost invariably provokes anxiety, which may take the
form of a situationally bound or situationally predisposed panic
attack. [0326] The person recognizes that the fear is excessive or
unreasonable. In children, this feature may be absent. [0327] The
feared social or performance situations are avoided or else are
endured with intense anxiety or distress. [0328] The avoidance,
anxious anticipation, or distress in the feared social or
performance situation (s) interferes significantly with the
person's normal routine, occupational (academic) functioning, or
social activities or relationships, or there is marked distress
about having the phobia. [0329] For individuals under the age 18
years, the duration is at least 6 months. [0330] The fear or
avoidance is not due to the direct physiological effects of a
substance (eg, a drug of abuse, a medication) or a general medical
condition and is not better accounted for by another mental
disorder. [0331] If a general medical condition or another mental
disorder is present, the fear in Criterion A is unrelated to
it.
[0332] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0333] i. Additional Pre-Treatments
[0334] If a patient is diagnosed and currently being treated with a
conventional treatment for the anxiety disorder, the patient will
need to be placed in a state of withdrawal, which includes, but is
not limited to, weaning the patient off of any pharmacotherapy
prescribed by the conventional treatment protocol. An exemplary
protocol is described below, and thus, it should be noted that the
invention is not limited to the use of such protocol.
[0335] Phobias are most commonly treated using a combination of
pharmacotherapy and cognitive therapy. Popular pharmacotherapy
treatments include benzodiazepines, beta-blockers, and selective
serotonin re-uptake inhibitors. Table 1 provides listings and
examples, including dosing information of various compounds in the
classes listed above that may be used to treat panic disorder and
will not be repeated herein.
[0336] ii. Placing a Patient in a State of Withdrawal
[0337] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0338] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.A Receptor Expression
[0339] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0340] d. Additional Treatment Options
[0341] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0342] e. Post-Treatment Phase of Protocol
[0343] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0344] f. Hypothetical Treatment Example 1
[0345] Male, 26 years old, under DSM IV criteria, has been
diagnosed as having a social phobia (or social anxiety
disorder).
[0346] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0347] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0348] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0349] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0350] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0351] g. Hypothetical Treatment Example 2
[0352] Male, 26 years old, under DSM IV criteria, has been
diagnosed as having social anxiety disorder. He is currently under
pharmacotherapy, with medications including paroxetine, 20 mg/day
and alprazolam, 0.25 mg/day on an as needed basis (maximum 4 mg in
24 hours).
[0353] Patient Preparation Step 1: Six weeks prior to scheduled
treatment, patient is instructed to decrease paroxetine dosage 10
mg/day for two weeks.
[0354] Four weeks prior to scheduled treatment, patient is
instructed to cease all medications, including alprazolain and
paroxetine.
[0355] Patient Preparation Step 2: Four weeks prior to scheduled
treatment, he is initiated on a scheduled finasteride
administration of 5 mg per day. Three days prior to scheduled
treatment, the finasteride administration is terminated and the
patient is instructed to not engage in any stress-inducing
activities or ingest any substances that would likely increase
neurosteroid production.
[0356] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0357] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0358] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0359] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
X. Example 4
Protocol for the Treatment of Obsessive Compulsive Disorder
[0360] a. Pre-Treatment/Patient Assessment Phase
[0361] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0362] i. Diagnosis of Obsessive Compulsive Disorder (OCD)
[0363] Obsessive compulsive disorder is a type of anxiety disorder
characterized by obsessions and/or compulsions. Obsessions are
distressing, repetitive thoughts or images that the individual
often realizes are senseless. Compulsions are repetitive behaviors
that the person feels forced or compelled into doing, in order to
relieve anxiety. OCD is characterized by either obsessions or
compulsions: [0364] Obsessions as defined by (A), (B), (C) and (D):
[0365] A. Recurrent and persistent thoughts, impulses, or images
that are experienced, at some time during the disturbance, as
intrusive and inappropriate and that cause marked anxiety or
distress. [0366] B. The thoughts, impulses or images are not simply
excessive worries about real-life problems. [0367] C. The person
attempts to ignore or suppress such thoughts, impulses or images,
or to neutralize them with some other thought or action. [0368] D.
The person recognizes that the obsessional thoughts, impulses or
images area product of his or her own mind (not imposed from
without as in thought insertion). [0369] Compulsions as defined by
(A) and (3): [0370] A. Repetitive behaviors (e.g., hand washing,
ordering, checking) or mental acts (e.g., praying, counting,
repeating words silently) that the person feels driven to perform
in response to an obsession, or according to rules that must be
applied rigidly. [0371] B. The behaviors or mental acts are aimed
at preventing or reducing distress or preventing some dreaded event
or situation; however, these behaviors or mental acts either are
not connected in a realistic way with what they are designed to
neutralize or prevent, or are clearly excessive. [0372] At some
point during the course of the disorder, the person has recognized
that the obsessions or compulsions are excessive or unreasonable.
Note: This does not apply to children. [0373] The obsessions or
compulsions cause marked distress, are time-consuming (more than 1
hour a day), or significantly interfere with the person's normal
routine, occupational (or academic) functioning, or usual social
activities or relationships. [0374] If another Axis I disorder is
present, the content of the obsessions or compulsions is not
restricted to it. [0375] 5. The disturbance is not due to the
direct physiological effects of a substance or a medical
condition.
[0376] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0377] i. Additional Pre-Treatments
[0378] If a patient is diagnosed and currently being treated with a
conventional treatment for the anxiety disorder, the patient will
need to be placed in a state of withdrawal, which includes, but is
not limited to, weaning the patient off of any pharmacotherapy
prescribed by the conventional treatment protocol. An exemplary
protocol is described below, and thus, it should be noted that the
invention is not limited to the use of such protocol.
[0379] The following guideline is adapted from
"Obsessive-Compulsive Disorder Patient/Family Handout" published at
http://www.psychguides.com/oche.php, which is herein incorporated
by reference.
[0380] OCD is typically treated with cognitive-behavioral
psychotherapy (CBT) and medication with pharmacotherapy, usually a
selective serotonin re-uptake inhibitor. Popular medications
include clomipramine, fluoxetine, fluvoxamine, paroxetine, and
sertraline.
[0381] It may also be useful to supplement the SSRI with an
anxiety-reducing medication, such as clonazepam or alprazolam, in
patients with a high level of anxiety. In addition, a high potency
neuroleptic, such as haloperidol or risperidone, may be used when
tics or thought-disorder symptoms are present.
[0382] It is recommended that a patient stop any medication
gradually.
[0383] ii. Placing a Patient in a State of Withdrawal
[0384] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0385] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.A Receptor Expression
[0386] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0387] d. Additional Treatment Options
[0388] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0389] e. Post-Treatment Phase of Protocol
[0390] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0391] f. Hypothetical Treatment Example 1
[0392] Female, 27 years old, under DSM IV criteria, has been
diagnosed as having Obsessive Compulsive Disorder.
[0393] Patient Preparation Six weeks prior to scheduled treatment,
female patient is administered oral contraceptives. One week prior
to scheduled treatment, the administration of oral contraceptives
is terminated. Three days prior to scheduled treatment, the patient
is instructed to not engage in any stress-inducing activities or
ingest any substances that would likely increase neurosteroid
production.
[0394] Day 1 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0395] Day 2 of Treatment: Female patient is administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0396] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0397] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0398] g. Hypothetical Treatment Example 2
[0399] Female, 27 years old, under DSM IV criteria, has been
diagnosed as having Obsessive Compulsive Disorder. Female patient
is currently undergoing cognitive behavioral therapy and
pharmacotherapy. She is currently taking paroextine 40 mg per
day.
[0400] Patient Preparation: Eight weeks prior to scheduled
treatment, patient is instructed to decrease paroxetine dosage to
20 mg/day for two weeks. Six weeks prior to scheduled treatment,
patient is instructed to further decrease paroxetine dosage to 10
mg/day for two weeks.
[0401] Four weeks prior to scheduled treatment, patient is
instructed to cease all medications for this course of treatment,
including paroxetine.
[0402] Additional Patient Preparation: Six weeks prior to scheduled
treatment, female patient is administered oral contraceptives. One
week prior to scheduled treatment, the administration of oral
contraceptives is terminated. Three days prior to scheduled
treatment, the patient is instructed to not engage in any
stress-inducing activities or ingest any substances that would
likely increase neurosteroid production,
[0403] Day 1 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0404] Day 2 of Treatment: Female patient is administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0405] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0406] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
XI. Example 5
Protocol for the Treatment of Post-Traumatic Stress Disorder
(PTSD)/Acute Stress Disorder
[0407] Developmental research is revealing that many brain and
hormonal changes may occur as a result of early, prolonged trauma,
and these changes contribute to difficulties with memory, learning,
and regulating impulses and emotions. Combined with a disruptive,
abusive home environment that does not foster healthy interaction,
these brain and hormonal changes may contribute to severe
behavioral difficulties (such as impulsivity, aggression, sexual
acting out, eating disorders, alcohol/drug abuse, and
self-destructive actions), emotional regulation difficulties (such
as intense rage, depression, or panic), and mental difficulties
(such as extremely scattered thoughts, dissociation, and amnesia).
As adults, these individuals often are diagnosed with depressive
disorders, personality disorders, or dissociative disorders.
Treatment of acute stress disorder often takes much longer than
with regular PTSD, may progress at a much slower rate, and requires
a sensitive and structured treatment program delivered by a trauma
specialist.
[0408] Psychiatric disorders that commonly co-occur with PTSD
include depression, alcohol/substance abuse, panic disorder, and
other anxiety disorders. Although crises that threaten the safety
of the survivor or others must be addressed first, the best
treatment results are achieved when both PTSD and the other
disorder(s) are treated together rather than one after the other.
This is especially true for PTSD and alcohol/substance abuse.
[0409] a. Pre-Treatment/Patient Assessment Phase
[0410] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0411] i. Diagnosis of Post-Traumatic Stress Disorder [0412] The
person has been exposed to a traumatic event in which both of the
following were present: [0413] The person experienced, witnessed or
was confronted with an event that involved actual or threatened
death or serious injury, or a threat to the physical integrity of
others AND [0414] The person's response involved intense fear,
helplessness or horror. Note: In children, this may be expressed
instead by disorganized or agitated behavior. [0415] The traumatic
event is persistently re-experienced in one (or more) of the
following ways: [0416] Recurrent and intrusive distressing
recollections of the event, including images, thoughts or
perceptions. Note: In young children, repetitive play may occur in
which themes or aspects of the trauma are expressed. [0417]
Recurrent distressing dreams of the event. Note: In children, there
may be frightening dreams without recognizable content. [0418]
Acting or feeling as if the traumatic event were recurring
(includes a sense of reliving the experience, illusions,
hallucinations and dissociative flashback episodes, including those
that occur on awakening or when intoxicated). Note: In young
children, trauma-specific reenactment may occur. [0419] Intense
psychological distress at exposure to internal or external cues
that symbolize or resemble an aspect of the traumatic event. [0420]
Physiological reactivity on exposure to internal or external cues
that symbolize or resemble an aspect of the traumatic event. [0421]
Persistent avoidance of stimuli associated with the trauma and
numbing of general responsiveness (not present before the trauma),
as indicated by three (or more) of the following: [0422] Efforts to
avoid thoughts, feelings or conversations associated with the
trauma [0423] Efforts to avoid activities, places or people that
arouse recollections of the trauma [0424] Inability to recall an
important aspect of the trauma [0425] Markedly diminished interest
or participation in significant activities [0426] Feeling of
detachment or estrangement from others [0427] Restricted range of
affect (eg, does not expect to have a career marriage, children or
a normal life span) [0428] Persistent symptoms of increased arousal
(not present before the trauma) as indicated by two (or more) of
the following: [0429] Difficulty falling or staying asleep [0430]
Irritability or outbursts of anger [0431] Difficulty concentrating
[0432] Hypervigilance [0433] Exaggerated startle response [0434]
Duration of the disturbance (symptoms in Criteria B, C and D) is
more than 1 month. [0435] The disturbance causes clinically
significant distress or impairment in social, occupational or other
important areas of functioning. [0436] Specify whether acute (the
duration of the symptoms is less than 3 months), chronic (the
duration of symptoms is 3 months or more), with delayed onset (if
the onset of symptoms is at least 6 months after the stressor).
[0437] ii. Diagnosis of Acute Stress Disorder [0438] The person has
been exposed to a traumatic event in which both of the following
were present: [0439] The person experienced, witnessed, or was
confronted with an event or events that involved actual or
threatened death or serious injury, or a threat the physical
integrity of self or others [0440] The person's response involved
intense fear, helplessness or horror [0441] Either while
experiencing or after experiencing the distressing event, the
individual has three (or more) of the following dissociative
symptoms: [0442] a subjective sense of numbing, detachment or
absence of emotional responsiveness [0443] a reduction in awareness
of his or her surroundings (eg, "being in a daze" derealization
[0444] depersonalization [0445] dissociative amnesia (e.g.,
inability to recall an important aspect of the trauma) [0446] The
traumatic event is persistently re-experienced in at least one of
the following ways: recurrent images, thought, dreams, illusions,
flashback episodes or a sense of reliving the experience; or
distress on exposure to reminders of the traumatic event. [0447]
Marked avoidance of the stimuli that arouse recollections of the
trauma (e.g., thoughts, feelings, conversations, activities,
places, people). [0448] Marked symptoms of anxiety or increased
arousal (e.g., difficulty sleeping, irritability, poor
concentration, hypervigilance, exaggerated startle response, motor
restlessness). [0449] The disturbance causes clinically significant
distress or impairment in social, occupational or other important
areas of functioning or impairs the individual's ability to pursue
some necessary task, such as obtaining necessary assistance or
mobilizing personal resources by telling family members about the
traumatic experience. [0450] The disturbance lasts for a minimum of
2 days and a maximum of 4 weeks and occurs within 4 weeks of the
traumatic event. [0451] The disturbance is not due to the direct
physiological effects of a substance (eg, a drug of abuse, a
medication) or a general medical condition, is not better accounted
for by brief psychotic disorder, and is not merely an exacerbation
of a preexisting Axis I or Axis II disorder.
[0452] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0453] i. Additional Pre-Treatments
[0454] If a patient is diagnosed and currently being treated with a
conventional treatment for the anxiety disorder, the patient will
need to be placed in a state of withdrawal, which includes, but is
not limited to, weaning the patient off of any pharmacotherapy
prescribed by the conventional treatment protocol. An exemplary
protocol is described below, and thus, it should be noted that the
invention is not limited to the use of such protocol.
[0455] The following treatment recommendations were adapted from
the guidelines provided by the United States Department of Veterans
Affairs, National Center for Post-Traumatic Stress Disorder. For
more information, please refer to
http://www.ncptsd.va.gov/facts/treatment/fs_treatment.html.
[0456] The treatment protocol includes psychological and
pharmacological treatments. Pharmacotherapy (medication) can reduce
the anxiety, depression, and insomnia often experienced with PTSD,
and in some cases, it may help relieve the distress and emotional
numbness caused by trauma memories. Several kinds of antidepressant
drugs have contributed to patient improvement in most (but not all)
clinical trials, although no particular drug has emerged as a
definitive treatment for PTSD.
[0457] Currently, there are no FDA approved medications for acute
stress reactions and the only FDA approved medication for PTSD is
sertraline. It is also extremely important to consider possible
drug interactions for individuals who are taking other prescribed
or over-the-counter medications.
[0458] In some cases, a clinician may need to prescribe
psychotropic medications even before he or she has completed the
medical and psychiatric evaluation. The acute use of medications
may be necessary when the survivor is dangerous, extremely
agitated, or psychotic. In such circumstances, the individual
should be taken to an emergency room. In the emergency room,
short-acting benzodiazepines (e.g. lorazepam) or high potency
neuroleptics (e.g. haldol) with minimal sedative, anticholinergic,
and orthostatic side effects may prove effective. Atypical
neuroleptics (e.g. risperidone), at relatively low doses, may also
be useful in treating impulsive aggression. Pharmacological agents
for the treatment of trauma-related arousal include benzodiazepines
and antiadrenergic agents such as clonidine, guanfacine and
propranolol.
[0459] Low doses of propranolol have also been successfully used to
combat stage fright and performance anxiety because it modulates
physical and cognitive manifestations of stress. However,
clinicians should prescribe clonidine, guanfacine and propranolol
judiciously for survivors with cardiovascular disease. This is
because these medications may reduce blood pressure. In addition,
clonidine may induce rebound hypertension if the client's blood
levels fall due to infrequent dosing or a sudden discontinuation.
Furthermore, these agents should not be prescribed to persons with
diabetes as they may interfere with counterregulatory hormone
responses to hypoglycemia.
[0460] Recent trauma survivors may also suffer from debilitating
symptoms of depression. Since all three symptom clusters of PTSD
respond to selective serotonin reuptake inhibitors (SSRIs), and
because depressive symptoms originating soon after trauma may
predict PTSD, it is recommended that SSRIs be considered for
persistent posttraumatic depression. In addition, SSRIs may be
useful for controlling anxiety and irritability. It is important to
note that traumatized women, compared to men, may be particularly
responsive to the beneficial effects of SSRIs. SSRIs as well as
other antidepressants should be administered in a "start low and go
slow" dosing regimen because some individuals may develop increased
anxiety or agitation in response to them. In addition, individuals
occasionally develop psychotic or manic symptoms in response to
SSRIs.
[0461] Some individuals have preexisting psychiatric disorders,
including preexisting PTSD, at the time that they experience
trauma. The most recent trauma may exacerbate these preexisting
conditions, making it essential to carefully assess the
individual's psychotherapeutic and pharmacological needs. It is
imperative that a clinician contact any other current treaters and
maintain continuity of care.
[0462] ii. Placing a Patient in a state of Withdrawal
[0463] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0464] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.A Receptor Expression
[0465] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0466] d. Additional Treatment Options
[0467] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0468] e. Post-Treatment Phase of Protocol
[0469] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0470] f. Hypothetical Treatment Example 1
[0471] Male, 47 years old, under DSM-IV criteria, has been
diagnosed as having post-traumatic stress disorder (PTSD).
[0472] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0473] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0474] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0475] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0476] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0477] g. Hypothetical Treatment Example 2
[0478] Male, 47 years old, under DSM IV criteria, has been
diagnosed as having post-traumatic stress disorder (PTSD). He is
currently undergoing cognitive-behavioral and pharmacotherapeutic
treatment, current medication is paroxetine 20 mg/day.
[0479] Patient Preparation Step 1: Six weeks prior to scheduled
treatment, patient is instructed to decrease paroxetine dosage 10
mg/day for two weeks.
[0480] Four weeks prior to scheduled treatment, patient is
instructed to cease all medications, including alprazolam and
paroxetine.
[0481] Patient Preparation Step 2: Four weeks prior to scheduled
treatment, he is initiated on a scheduled finasteride
administration of 5 mg per day. Three days prior to scheduled
treatment, the finasteride administration is terminated and the
patient is instructed to not engage in any stress-inducing
activities or ingest any substances that would likely increase
neurosteroid production.
[0482] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0483] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0484] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0485] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
XII. Example 6
Protocol for the Treatment of Eating Disorders
[0486] Eating disorders, also considered psychological disorders,
typically include elements of maladaptive eating patterns.
Sufferers may experience withdrawal or withdrawal-like symptoms if
they alter their diet suddenly. Anorexia nervosa, bulimia nervosa
and other eating disorders, such as binge-eating, may be methods
for artificially creating stress in one's system, thus increasing
progesterone/allopregnanolone, thereby decreasing anxiety.
[0487] The primary physiological characteristics of anorexia
nervosa are voluntary starvation and exercise stress. In addition
to intentional starvation, subjects will also take part in a high
level of physical activity. Anorexia nervosa also has a negative
impact on the immune system and the central nervous system (CNS)
and is also thought to be linked to serotonin and dopamine
abnormalities.
[0488] The onset of anorexia may have a genetic component, with a
certain gene linked to abnormalities with the neurotransmitter
chemical serotonin. Such genetic characteristics might potentially
equate to an easier path towards overly high serotonin levels, thus
instilling heightened levels of anxiety and stress. Biologically,
when a person is in a state of starvation, their levels of
serotonin decrease, and thence increase again upon the consumption
of food because of the tryptophan amino acids contained therein
(tryptophan is used by the body to synthesize serotonin). It is
thus hypothesized that the anorectic is conditioned into avoiding
food to reduce his or her anxiety. Starvation is thus the
stress-inducer, causing an increase in progesterone. Both eating
and purging acutely induce stress to normalize anxiety.
[0489] Bulimia nervosa is a psychological condition in which the
subject engages in recurrent binge eating followed by intentionally
doing one or more of the following in order to compensate for the
intake of food and prevent weight gain: vomiting; inappropriate use
of laxatives, enemas, diuretics or other medication; excessive
exercising; and fasting. Purging is a quicker method of increasing
stress and thus progesterone. The compulsion to purge results in
induced stress and normalized anxiety and thus, a greater feeling
of control in the individual.
[0490] A person is characterized as bulimic when he or she feels
incapable of controlling the urge to binge, even during the binge
itself, when he or she consumes a larger amount of food that a
person would normally consume at one sitting, and when such
behavior occurs at least twice per week for three months. Bulimia
is often less about food, and more about dealing with deep
psychological issues and profound feelings of lack of control.
[0491] The following diagnosis and treatment guidelines are adapted
from the National Collaborating Centre for Mental Health (Eating
disorders. Core interventions in the treatment and management of
anorexia nervosa, bulimia nervosa and related eating disorders.
Leicester (UK): British Psychological Society; 2004. 260 p. [408
references]).
[0492] a. Pre-Treatment/Patient Assessment Phase
[0493] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0494] i. Diagnosis of Eating Disorders
[0495] Assessment of people with eating disorders should be
comprehensive and include physical, psychological, and social needs
and a comprehensive assessment of risk to self. The level of risk
to the patient's mental and physical health should be monitored as
treatment progresses because it may change--for example, following
weight gain or at times of transition between services in cases of
anorexia nervosa.
[0496] Target groups for screening should include young women with
low body mass index (BMI) compared with age norms, patients
consulting with weight concerns who are not overweight, women with
menstrual disturbances or amenorrhoea, patients with
gastrointestinal symptoms, patients with physical signs of
starvation or repeated vomiting, and children with poor growth.
[0497] When screening for eating disorders one or two simple
questions should be considered for use with specific target groups
(for example, "Do you think you have an eating problem?" and "Do
you worry excessively about your weight?").
[0498] Young people with type 1 diabetes and poor treatment
adherence should be screened and assessed for the presence of an
eating disorder.
[0499] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0500] i. Additional Pre-Treatments
[0501] If a patient is diagnosed and currently being treated with a
conventional treatment for the anxiety disorder, the patient will
need to be placed in a state of withdrawal, which includes, but is
not limited to, weaning the patient off of any pharmacotherapy
prescribed by the conventional treatment protocol. An exemplary
protocol is described below, and thus, it should be noted that the
invention is not limited to the use of such protocol.
[0502] 1. Typical Anorexia Nervosa Treatment
[0503] There is a very limited evidence base for the
pharmacological treatment of anorexia nervosa. A range of drugs may
be used in the treatment of comorbid conditions but caution should
be exercised in their use given the physical vulnerability of many
people with anorexia nervosa.
[0504] Medication should not be used as the sole or primary
treatment for anorexia nervosa. Caution should be exercised in the
use of medication for comorbid conditions such as depressive or
obsessive-compulsive features, as they may resolve with weight gain
alone.
[0505] When medication is used to treat people with anorexia
nervosa, the side effects of drug treatment (in particular, cardiac
side effects) should be carefully considered because of the
compromised cardiovascular function of many people with anorexia
nervosa.
[0506] Health care professionals should be aware of the risk of
drugs that prolong the QTc interval on the electrocardiogram (ECG)
(for example, antipsychotics, tricyclic antidepressants, macrolide
antibiotics, and some antihistamines). In patients with anorexia
nervosa at risk of cardiac complications, the prescription of drugs
with side effects that may compromise cardiac functioning should be
avoided. If the prescription of medication that may compromise
cardiac functioning is essential, ECG monitoring should be
undertaken.
[0507] All patients with a diagnosis of anorexia nervosa should
have an alert placed in their prescribing record concerning the
risk of side effects.
[0508] In most patients with anorexia nervosa, an average weekly
weight gain of 0.5-1 kg in inpatient settings and 0.5 kg in
outpatient settings should be an aim of treatment. This requires
about 3,500 to 7,000 extra calories a week.
[0509] Regular physical monitoring, and in some cases treatment
with a multi-vitamin/multi-mineral supplement in oral form, is
recommended for people with anorexia nervosa during both inpatient
and outpatient weight restoration.
[0510] Total parenteral nutrition should not be used for people
with anorexia nervosa, unless there is significant gastrointestinal
dysfunction.
[0511] Pregnant women with either current or remitted anorexia
nervosa may need more intensive prenatal care to ensure adequate
prenatal nutrition and fetal development.
[0512] 2. Typical Builimia Nervosa Treatment
[0513] As an alternative or additional first step to using an
evidence-based self-help program, adults with bulimia nervosa may
be offered a trial of an antidepressant drug.
[0514] Patients should be informed that antidepressant drugs can
reduce the frequency of binge eating and purging, but the long-term
effects are unknown. Any beneficial effects will be rapidly
apparent.
[0515] Selective serotonin reuptake inhibitors (SSRIs)
(specifically fluoxetine) are the drugs of first choice for the
treatment of bulimia nervosa in terms of acceptability,
tolerability, and reduction of symptoms. For people with bulimia
nervosa, the effective dose of fluoxetine is higher than for
depression (60 mg daily). No drugs, other than antidepressants, are
recommended for the treatment of bulimia nervosa.
[0516] 3. Typical Treatment of Binge Eating Disorder
[0517] As an alternative or additional first step to using an
evidence based self-help programme, consideration should be given
to offering a trial of an SSRI antidepressant drug to patients with
binge eating disorder.
[0518] Patients with binge eating disorders should be informed that
SSRIs can reduce binge eating, but the long-term effects are
unknown. Antidepressant drug treatment may be sufficient treatment
for a limited subset of patients.
[0519] ii. Placing a Patient in a State of Withdrawal
[0520] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0521] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.A Receptor Expression
[0522] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0523] d. Additional Treatment Options
[0524] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0525] e. Post-Treatment Phase of Protocol
[0526] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0527] f. Hypothetical Treatment Example 1 Anorexia, Bulimia, or
Binge Eating Disorder
[0528] Female, 26, under DSM-IV criteria, has been diagnosed as
having an eating disorder, and more specifically, anorectic and
bulimic episodes.
[0529] Patient Preparation: In one embodiment, six weeks prior to
scheduled treatment, female patient is administered oral
contraceptives. One week prior to scheduled treatment, the
administration of oral contraceptives is terminated. Three days
prior to scheduled treatment, the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0530] In another embodiment, treatment protocol of the present
invention is begun when progesterone levels are low in a female
patient. Preferably, this time window begins on the day of
menstruation and lasts for about ten days. The ideal time window of
minimal progesterone levels has been described in detail above. The
responsible treating physician should examine each patient
individually and determine, using proper diagnostic tests and
patient history, when the optimal low progesterone time window is
for that particular patient. Thus, the protocol outlined herein is
exemplary.
[0531] Day 1 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of his health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0532] Day 2 of Treatment: Female patient is administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0533] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day. Patient
is then instructed to return to treatment center in 28 days. Again,
the treating physician should ensure that the patient is in a
minimal progesterone time window.
[0534] Day 28+1 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0535] Day 28+2 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0536] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0537] g. Hypothetical Treatment Example 2--Bulimia Nervosa
[0538] Female, 26, under DSM-IV criteria, has been diagnosed as
having an eating disorder, and more specifically, bulimic episodes.
She is currently under treatment and taking 60 mg/day fluoxetine
hydrochloride, administered in the morning.
[0539] Patient Preparation Sixteen weeks prior to scheduled
treatment, patient is advised to reduce the dosage of fluoxetine to
30 mg/day for four weeks. Twelve weeks prior to scheduled
treatment, the dosage is further lowered to 10 mg/day for four
weeks. Eight weeks prior to scheduled treatment, patient is advised
to stop taking all medications, including fluoxetine.
[0540] Additional Patient Preparation: In one embodiment, six weeks
prior to scheduled treatment, female patient is administered oral
contraceptives. One week prior to scheduled treatment, the
administration of oral contraceptives is terminated. Three days
prior to scheduled treatment, the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0541] In another embodiment, treatment protocol of the present
invention is begun when progesterone levels are low in a female
patient. Preferably, this time window begins on the day of
menstruation and lasts for about ten days. The ideal time window of
minimal progesterone levels has been described in detail above. The
responsible treating physician should examine each patient
individually and determine, using proper diagnostic tests and
patient history, when the optimal low progesterone time window is
for that particular patient. Thus, the protocol outlined herein is
exemplary.
[0542] Day 1 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0543] Day 2 of Treatment: Female patient is administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0544] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day. Patient
is then instructed to return to treatment center in 28 days. Again,
the treating physician should ensure that the patient is in a
minimal progesterone time window.
[0545] Day 28+1 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0546] Day 28+2 of Treatment: Female patient is administered
flumazenil, via infusion, at an amount less than 15 mg/day. The
patient's heart rate and blood pressure are monitored, along with
the patient's own qualitative assessment of her health, including,
but not limited to, subjective feelings of anxiety. The total dose
and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0547] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0548] The above examples are merely illustrative of the many
applications of the system of present invention. Although only a
few embodiments of the present invention have been described
herein, it should be understood that the present invention might be
embodied in many other specific forms without departing from the
spirit or scope of the invention. Therefore, the present examples
and embodiments are to be considered as illustrative and not
restrictive, and the invention is not to be limited to the details
given herein, but may be modified within the scope of the appended
claims. All patents, publications and abstracts cited above are
incorporated herein by reference in their entirety.
TABLE-US-00001 TABLE 1 EXEMPLARY LISTING OF PHARMACOLOGICAL
COMPOUNDS AND SUGGESTED DOSAGES FOR USE WITH THE PRESENT INVENTION
SECONDARY EXEMPLARY DRUG DRUG CLASS DRUG CLASS LISTING DOSAGE
ANALGESICS OPIATES ALFENTANIL FOR USE DURING GENERAL ANESTHESIA
(PAINKILLERS) ALFENTA (alfentanil SPONTANEOUSLY BREATHING/ASSISTED
VENTILATION: hydrochloride) Induction of Analgesia: 8-20 mcg/kg;
Maintenance of Analgesia: 3-5 mcg/kg q 5-20 min or 0.5 to 1
mcg/kg/min; Total dose: 8-40 mcg/kg ASSISTED OR CONTROLLED
VENTILATION: Incremental Injection (to attenuate response to
laryngoscopy and intubation): Induction of Analgesia: 20-50 mcg/kg;
Maintenance of Analgesia: 5-15 mcg/kg q 5-20 min; Total dose: Up to
75 mcg/kg. Continuous Infusion: (To provide attenuation of response
to intubation and incision): Infusion rates are variable and should
be treated to the desired clinical effect. Induction of Analgesia:
50-75 mcg/kg; Maintenance of Analgesia: 0.5 to 3 mcg/kg/min
(Average rate 1 to 1.5 mg/kg/min); Total dose: Dependent on
duration of procedure. Anesthetic Induction: Induction of
Analgesia: 130-245 mcg/kg; Maintenance of Analgesia: 0.5 to 1.5
mcg/kg/min or general anesthetic; Total dose: Dependent on duration
of procedure. At these doses, truncal rigidity should be expected
and a muscle relaxant should be utilized; Administer slowly (over 3
minutes); Concentration of inhalation agents reduced by 30-50% for
initial hour. MONITORED ANESTHESIA CARE (MAC) (For sedated and
responsive, spontaneously breathing patients): Induction of M.C.
3-8 mcg/kg; Maintenance of M.C. 3-5 mcg/kg q 5-20 min or 0.25 to 1
mcg/kg/min; Total dose: 3-40 mcg/kg BUPRENORPHINE Administered
sublingually as a single daily dose in the range of 12 to 16
mg/day. Buprenorphine is also delivered transdermally in 25, 50,
and 75 mcg/ hour. BUTORPHANOL This formulation of butorphanol is
administered every 3-4 hours either as a nasal spray or injected
into the buttock or hip muscle or into a vein. The FDA does not
regulate Stadol .RTM. in most states. CODEINE (also METHYL Codeine
and codeine-combo preparations are usually taken every 4-6
MORPHINE) hours. Adults: 15 to 60 mg every 4 to 6 hours (usual
adult dose, 30 mg). Children: 1 Year of Age and Older - 0.5 mg/kg
of b.d. weight or 15 mg/m2 of b.d. surface every 4 to 6 hours. 200
mg (oral) of codeine is about equal to 30 mg (oral) of morphine.
CODEINON See Hydrocodone for details. PROPOXYPHENE Acetaminophen
(Tylenol) and propoxyphene. (DARVOCET) It is formulated as a tablet
taken every 4 hours by mouth. DEXTROPROPOXYPHENE Oral analgesic
potency is one-half to one-third that of codeine, with 65 mg
approximately equivalent to about 600 mg of aspirin.
Dextropropoxyphene is prescribed for relief of mild to moderate
pain. HEROIN ILLICIT SUBSTANCE/NO APPROVED DOSING
(DIACETYLMORPHINE) DIHYDROCODEINE Dihydrocodeine is approximately
twice as potent as codeine; this is taken into consideration while
dosing dihydrocodeine. Codeine Dosage: For the treatment of mild
pain to moderate pain: Adults: 15-60 mg PO (oral) every 4-6 hours.
For the treatment of non- productive cough: Adults: 10-20 mg PO
(oral) every 4-6 hours. For the treatment of diarrhoea: Adults: 30
mg PO (oral) FENTANYL Route of administration: patch, injected,
oral transmucosal. The patch is usually changed every 72 hours or
as directed by physician. Fentanyl (DURAGESIC .RTM.) should ONLY be
used in patients who are already receiving opioid therapy, who have
demonstrated opioid tolerance, and who require a total daily dose
at least equivalent to DURAGESIC .RTM. 25 mcg/h. Patients who are
considered opioid- tolerant are those who have been taking, for a
week or longer, at least 60 mg of morphine daily, or at least 30 mg
of oral oxycodone daily, or at least 8 mg oral hydromorphone daily,
or an equianalgesic dose of another opioid. HYDROCODONE Five mg of
hydrocodone is equivalent to 30 mg of codeine when DIHYDROCODEINONE
administered orally. Also, a dose of 15 mg (1/4 gr) of hydrocodone
is equivalent to 10 mg (1/6 gr) of morphine. The typical
therapeutic dose of 5 to 10 mg is pharmacologically equivalent to
30 to 60 mg of oral codeine. HYDROMORPHONE Dilaudid .RTM. is
formulated as oral tablets and liquid, rectal suppository,
intra-muscular (buttock or hip muscle) injection, and intravenous
(I.V.) solution. Dosing is every 4-6 hours for the oral forms and
every 6-8 hours for the suppository. An I.V. drip allows for
continuous administration and around-the-clock pain relief. It can
be given intravenously, intramuscularly, rectally, or orally. LAAM
The initial dose street addicts should be 20 to 40 mg. Each
Levomethadyl Acetate subsequent dose, administered at 48- or
72-hour intervals, may be Hydrochloride, also known as adjusted in
increments of 5 to 10 mg until a pharmacokinetic and
Levo-alpha-acetylmethadol or pharmacodynamic steady-state is
reached. Patients dependent on Levacetylmethadol (LAM) methadone
may require higher initial doses. METHADONE It comes as tablets,
dispersible tablets, liquid, and liquid concentrate. Patients take
it every 3-4 hours for severe pain and every 6-8 hours for chronic
pain. MORPHINE and NO APPROVED DOSING FOR PURE MORPHINE. SEE
MORPHINONE SALTS. MORPHINE SULFATE MS Contin .RTM. comes in the
form of tablets, capsules, liquid, and rectal suppository, which
are taken every 4 hours. Long-acting tablets and capsules can be
taken every 8-12 hours or 1-2 per day, respectively. OPIUM
(NATURAL) ILLEGAL - NO FDA RECOMMENDED USAGE OXYCODONE OxyContin
.RTM. comes in liquid and tablet forms taken every 6 hours.
Long-acting tablets are available to take every 12 hours.
OXYMORPHONE Injection: Subcutaneous or intramuscular
administration: initially 1 mg to 1.5 mg, repeated every 4 to 6
hours as needed. Intravenous: 0.5 mg initially. For analgesia
during labor 0.5 mg to 1 mg intramuscularly is recommended. Rectal
Suppositories: One suppository, 5 mg, every 4 to 6 hours. PETHIDINE
(MEPERIDINE) Adults: The usual dosage is 50 mg to 150 mg
intramuscularly, subcutaneously, or orally, every 3 or 4 hours as
necessary. Children: The usual dosage is 0.5 mg/lb to 0.8 mg/lb
intramuscularly, subcutaneously, or orally up to the adult dose,
every 3 or 4 hours as necessary. REMIFENTANIL During Induction of
Anesthesia: ULTIVA should be administered at an infusion rate of
0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the
induction of anesthesia. If endotracheal intubation is to occur
less than 8 minutes after the start of the infusion of ULTIVA, then
an initial dose of 1 mcg/kg may be administered over 30 to 60
seconds. For exact dosing for induction, maintenance and
continuation of general anesthesia, including special cases, please
refer to FDA Documents. SUFENTANIL Not more than 3 total doses.
Each dose must be at least one hour apart. THEBAINE Thebaine is not
used therapeutically, but is converted into a variety of compounds
including codeine, hydrocodone, hydromorphone, oxycodone,
oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and
etorphine. It is controlled in Schedule II of the Controlled
Substances Act as well as under international law. TRAMADOL
Tramadol is approximately 10% as potent as morphine, when given by
the IV/IM route. Oral doses range from 50-400 mg daily, with up to
600 mg daily when given IV/IM. TETRAHYRDOC MARINOL Marinol: widely
available through prescription. It comes in the ANNIBINOL/ form of
a pill and is also being studied by researchers for suitability THC
via other delivery methods, such as an inhaler or patch. The active
THC and some ingredient of Marinol is synthetic THC, which has been
found to other relieve the nausea and vomiting associated with
chemotherapy and cannibinoids, have the loss of appetite associated
with various other disease states. analgesic properties. THC -
Herbal and Synthetic ILLICIT SUBSTANCE - NO FDA-APPROVED DOSAGE
KETAMINE Intravenous Route: The initial dose of ketamine
administered intravenously may range from 1 mg/kg to 4.5 mg/kg (0.5
to 2 mg/lb). The average amount required to produce five to ten
minutes of surgical anesthesia has been 2 mg/kg (1 mg/lb).
Intramuscular Route: The initial dose of ketamine administered
intramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb). A
dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of
surgical anesthesia. BARBITURATES ALLOBARBITAL MRTD (Maximum
Recommended Therapeutic Dose) - 3.33000 mg/kg- body weight (bw)/day
based upon an average adult weighing 60 kg. AMOBARBITAL Defined
Daily Dose - 0.1 g, No data available from FDA. APROBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) - 2.67000 mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg. For trouble in
sleeping: Adults-40 to 160 milligrams (mg) at bedtime. For daytime
sedation: Adults-40 mg three times a day. BARBEXACLONE 100 mg of
barbexaclone is equivalent to 60 mg of phenobarbital. BARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- (VERONAL) body
weight (bw)/day based upon an average adult weighing 60 kg-
10.00000 BUTABARBITAL Butabarbital Oral is used to treat the
following: Severe Anxiety, Additional Agent to Induce General
Anesthesia, Abnormal Trouble Sleeping MRTD (Maximum Recommended
Therapeutic Dose) in mg/kg- body weight (bw)/day based upon an
average adult weighing 60 kg - 2.000 BUTALBITAL MRTD (Maximum
Recommended Therapeutic Dose) in mg/kg- Butalbital, 5-allyl-5- body
weight (bw)/day based upon an average adult weighing
isobutylbarbituric acid. 60 kg - 5.000 COMMON COMBINATIONS INCLUDE:
Butalbital and acetaminophen butalbital, acetaminophen, and
caffeine butalbital and aspirin butalbital, aspirin, and caffeine
BUTOBARBITAL 50 mg of Butobarbital is equivalent to 10 mg of
Diazepam; Acc. to (SONERYL) Nordic Statistics on Medicines, the
Defined Daily Dose of Butobarbital is 150 mg. No data available
from FDA. CYCLOBARBITAL MRTD (Maximum Recommended Therapeutic Dose)
in mg/kg- body weight (bw)/day based upon an average adult weighing
60 kg - 6.67000 ETHALLOBARBITAL N.A. HEPTABARBITAL Defined Daily
Dose - 0.2 g, No data available from FDA. HEXOBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg - 8.33000
MEPHOBARBITAL Epilepsy: Average dose for adults: 400 mg to 600 mg
daily; children (METHYLPHENOBARBITAL) under 5 years: 16 mg to 32 mg
three or four times daily; children over 5 years: 32 mg to 64 mg
three or four times daily. Sedation: Adults: 32 mg to 100 mg
optimum dose, 50 mg three to four times daily. Children: 16 mg to
32 mg three to four times daily. METHARBITAL METHOHEXITAL For
induction of anesthesia, a 1% solution is administered at a rate of
about 1 mL/5 seconds. The dose required for induction may range
from 50 to 120 mg or more but averages about 70 mg. The usual
dosage in adults ranges from 1 to 1.5 mg/kg. Maintenance of
anesthesia may be accomplished by intermittent injections of the 1%
solution or, more easily, by continuous intravenous drip of a 0.2%
solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL
of a 1% solution) may be given as required, usually every 4 to 7
minutes. For continuous drip, the average rate of administration is
about 3 mL of a 0.2% solution/minute (1 drop/second). PENTOBARBITAL
The usual adult dosage of NEMBUTAL Sodium Solution is 150 to 200 mg
as a single IM injection; the recommended pediatric dosage ranges
from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg.
The rate of IV injection should not exceed 50 mg/min for
pentobarbital sodium. PHENOBARBITAL Pediatric Oral Dosage (as
recommended by the American Academy of Pediatrics): Preoperative: 1
to 3 mg/kg. Adult Oral Dosage: Daytime sedative: 30 to 120 mg daily
in 2 to 3 divided doses. Bedtime hypnotic: 100 to 320 mg.
Anticonvulsant: 50 to 100 mg 2 to 3 times daily.
PRIMIDONE Adult Dosage: Patients 8 years of age and older who have
received no previous treatment may be started on primidone
according to the following regimen using Primidone 250 mg tablets.
Days 1-3: 100 to 125 mg at bedtime; Days 4-6: 100 to 125 mg b.i.d.;
Days 7-9: 100 to 125 mg t.i.d.; Day 10-maintenance; 250 mg t.i.d.
For most adults and children 8 years of age and over, the usual
maintenance dosage is three to four 250 mg primidone tablets daily
in divided doses (250 mg t.i.d. or q.i.d.). If required, an
increase to five or six 250 mg tablets daily may be made but daily
doses should not exceed 500 mg q.i.d. Pediatric Dosage: For
children under 8 years of age, the following regimen may be used:
Days 1-3: 50 mg at bedtime; Days 4-6: 50 mg b.i.d.; Days 7-9: 100
mg b.i.d.; Day 10-maintenance: 125. mg t.i.d. to 250 mg t.i.d. For
children under 8 years of age, the usual maintenance dosage is 125
to 250 mg three times daily, or 10-25 mg/kg/day in divided doses.
SECOBARBITAL For oral dosage form (capsules): For trouble in
sleeping: Adults-100 milligrams (mg) at bedtime. Children-Dose must
be determined by your doctor. For daytime sedation: Adults-30 to 50
mg three or four times a day. Children-Dose is based on body weight
or size and must be determined by your doctor. The usual dose is 2
mg per kilogram (kg) (0.9 mg per pound) of body weight three times
a day. For sedation before surgery: Adults-200 to 300 mg one or two
hours before surgery. Children-Dose is based on body weight and
must be determined by your doctor. The usual dose is 2 to 6 mg per
kg (0.9 to 2.7 mg per pound) of body weight one or two hours before
surgery. However, the dose is usually not more than 100 mg. For
injection dosage form: For trouble in sleeping: Adults-100 to 200
mg injected into a muscle, or 50 to 250 mg injected into a vein.
Children-Dose is based on body weight or size and must be
determined by your doctor. The usual dose is 3 to 5 mg per kg (1.4
to 2.3 mg per pound) of body weight, injected into a muscle.
However, the dose is usually not more than 100 mg. For sedation
before dental procedures: Adults-Dose is based on body weight and
must be determined by your doctor. The usual dose is 1.1 to 2.2 mg
per kg (0.5 to 1 mg per pound) of body weight, injected into a
muscle ten to fifteen minutes before the procedure. Children-Dose
must be determined by your dentist. For sedation before a nerve
block: Adults-100 to 150 mg, injected into a vein. For sedation
before surgery: Children-Dose is based on body weight and must be
determined by your doctor. The usual dose is 4 to 5 mg per kg (1.8
to 2.3 mg per pound) of body weight, injected into a muscle.
TALBUTAL MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
(Lotusate .RTM.), also called 5-allyl- body weight (bw)/day based
upon an average adult weighing 5-sec-butylbarbituric acid. 60 kg -
3.30000 THIOBARBITAL N.A. THIOPENTAL Use in Anesthesia: Moderately
slow induction can usually be Pentothal (Thiopental Sodium
accomplished in the "average" adult by injection of 50 to 75 mg for
Injection, USP). (2 to 3 mL of a 2.5% solution) at intervals of 20
to 40 seconds, depending on the reaction of the patient. Once
anesthesia is established, additional injections of 25 to 50 mg can
be given whenever the patient moves. Use in Convulsive States: For
the control of convulsive states following anesthesia (inhalation
or local) or other causes, 75 to 125 mg (3 to 5 mL of a 2.5%
solution) should be given as soon as possible after the convulsion
begins. Convulsions following the use of a local anesthetic may
require 125 to 250 mg of Pentothal given over a ten minute period.
Use in Psychiatric Disorders: For narcoanalysis and narcosynthesis
in psychiatric disorders, premedication with an anticholinergic
agent may precede administration of Pentothal. After a test dose,
Pentothal (Thiopental Sodium for Injection, USP) is injected at a
slow rate of 100 mg/mm (4 mL/min of a 2.5% solution) with the
patient counting backwards from 100. Shortly after counting becomes
confused but before actual sleep is produced, the injection is
discontinued. Allow the patient to return to a semidrowsy state
where conversation is coherent. Alternatively, Pentothal may be
administered by rapid I.V. drip using a 0.2% concentration in 5%
dextrose and water. At this concentration, the rate of
administration should not exceed 50 mL/min. VINBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- Vinbarbital
(5-Ethyl-5-(1- body weight (bw)/day based upon an average adult
weighing methyl-1-butenyl)barbituric 60 kg - 3.33000 acid).
VINYLBITAL Defined Daily Dose - 0.15 g, No data available from FDA.
Butylvinyl BENZODIAZEPINES ALPRAZOLAM Dosage Depends on Disorder:
Oral (For anxiety or nervous tension): Start: 0.25 mg to 0.5 mg 3
times daily. Maximum: 4 mg in 24 hours. Oral (For panic disorder):
Start: 0.5 mg 3 times daily. Increases: 1 mg daily in 3 to 4 day
intervals. Maximum: 10 mg in 24 hours. BROMAZEPAM Not commercially
available in the U.S. BROTIZOLAM Brotizolam is not approved for
sale in the United States or Canada. CAMAZEPAM Defined Daily Dose -
30 mg, No data available from FDA. CHLORDIAZEPOXIDE For relief of
mild and moderate anxiety disorders and symptoms of anxiety: 5 mg
or 10 mg, 3 or 4 times daily. For relief of server anxiety
disorders and symptoms of anxiety: 20 mg or 25 mg, 3 or 4 times
daily. Geriatric patients or in the presence of debilitating
disease: 5 mg, 2 to 4 times daily. CLONAZEPAM Seizure Disorders:
Adults: The initial dose for adults with seizure disorders should
not exceed 1.5 mg/day divided into three doses. Dosage may be
increased in increments of 0.5 to 1 mg every 3 days until seizures
are adequately controlled or until side effects preclude any
further increase. Maintenance dosage must be individualized for
each patient depending upon response. Maximum recommended daily
dose is 20 mg. Pediatric Patients: Klonopin is administered orally.
In order to minimize drowsiness, the initial dose for infants and
children (up to 10 years of age or 30 kg of body weight) should be
between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day
given in two or three divided doses. Dosage should be increased by
no more than 0.25 to 0.5 mg every third day until a daily
maintenance dose of 0.1 to 0.2 mg/kg of body weight has been
reached, unless seizures are controlled or side effects preclude
further increase. Whenever possible, the daily dose should be
divided into three equal doses. If doses are not equally divided,
the largest dose should be given before retiring. Panic Disorder:
Adults: The initial dose for adults with panic disorder is 0.25 mg
bid. An increase to the target dose for most patients of 1 mg/day
may be made after 3 days. The recommended dose of 1 mg/day is based
on the results from a fixed dose study in which the optimal effect
was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that
study were less effective than the 1 mg/day dose and were
associated with more adverse effects. Nevertheless, it is possible
that some individual patients may benefit from doses of up to a
maximum dose of 4 mg/day, and in those instances, the dose may be
increased in increments of 0.125 to 0.25 mg bid every 3 days until
panic disorder is controlled or until side effects make further
increases undesired. To reduce the inconvenience of somnolence,
administration of one dose at bedtime may be desirable. Treatment
should be discontinued gradually, with a decrease of 0.125 mg bid
every 3 days, until the drug is completely withdrawn. CLOTIAZEPAM
Clotiazepam is not approved for sale in the United States or Canada
CLORAZEPATE ORAL: START: 15 mg/daily INCREASES: As needed. MAXIMUM:
60 mg in 24 hours CLOXAZOLAM Cloxazolam is not approved for sale in
the United States or Canada. DELORAZEPAM Defined Daily Dose - 3 mg,
No data available from FDA. DIAZEPAM Management of Anxiety
Disorders and Relief of Symptoms of Anxiety: Depending upon
severity of symptoms - 2 mg to 10 mg, 2 to 4 times daily.
Symptomatic Relief in Acute Alcohol Withdrawal: 10 mg, 3 or 4 times
during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as
needed. Adjunctively for Relief of Skeletal Muscle Spasm: 2 mg to
10 mg, 3 or 4 times daily. Adjunctively in Convulsive Disorders. 2
mg to 10 mg, 2 to 4 times daily. Geriatric Patients, or in the
presence of debilitating disease: 2 mg to 2.5 mg, 1 or 2 times
daily initially; increase gradually as needed and tolerated.
Pediatric patients: Because of varied responses to CNS-acting
drugs, initiate therapy with lowest dose and increase as required.
Not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3
or 4 times daily initially; increase gradually as needed and
tolerated. ESTAZOLAM The recommended initial dose for adults is 1
mg at bedtime; however, some patients may need a 2 mg dose. In
healthy elderly patients, 1 mg is also the appropriate starting
dose, but increases should be initiated with particular care. In
small or debilitated older patients, a starting dose of 0.5 mg,
while only marginally effective in the overall elderly population,
should be considered. ETIZOLAM Etizolam is not approved for sale in
the United States or Canada. FLUDIAZEPAM Defined Daily Dose - 0.75
mg, No data available from FDA. FLUNITRAZEPAM Flunitrazepam has not
been approved by the Food and Drug Administration for medical use
in the United States. It is available only by private prescription
in the United Kingdom FLURAZEPAM Dosage should be individualized
for maximal beneficial effects. The usual adult dosage is 30 mg
before retiring. In some patients, 15 mg may suffice. In elderly
and/or debilitated patients, 15 mg is usually sufficient for a
therapeutic response HALAZEPAM For oral dosage form (tablets): For
anxiety: Adults-20 to 40 milligrams (mg) three or four times a day.
Children younger than 18 years of age-Use and dose must be
determined by your doctor. Older adults-20 mg one or two times a
day. HALOXAZOLAM Defined Daily Dose - 7.50 mg, No data available
from FDA. LOPRAZOLAM It is available in 1 mg tablets. The usual
adult dose is 1-2 mg at bedtime, the higher dose being recommended
for patients who have previously been treated with benzodiazepines
for severe persistent insomnia. An initial dose of 0.5 mg-1.0 mg is
recommended in elderly and debilitated patients. LOREZEPAM The
usual range is 2 to 6 mg/day given in divided doses, the largest
dose being taken before bedtime, but the daily dosage may vary from
1 to 10 mg/day. For anxiety, most patients require an initial dose
of 2 to 3 mg/day given b.i.d. or t.i.d. For insomnia due to anxiety
or transient situational stress, a single daily dose of 2 to 4 mg
may be given, usually at bedtime. For elderly or debilitated
patients, an initial dosage of 1 to 2 mg/day in divided doses is
recommended, to be adjusted as needed and tolerated. MEDAZEPAM
Defined daily dose as used in the Nordic Statistics on Medicines -
20 mg; No data available from FDA. MIDAZOLAM For preoperative
sedation/anxiolysis/amnesia. Intramuscular - The recommended
premedication dose of VERSED for good risk (ASA Physical Status I
& II) adult patients below the age of 60 years is 0.07 to 0.08
mg/kg IM (approximately 5 mg IM) administered up to 1 hour before
surgery. The dose must be individualized and reduced when IM VERSED
is administered to patients with chronic obstructive pulmonary
disease, other higher risk surgical patients, patients 60 or more
years of age, and patients who have received concomitant narcotics
or other CNS depressants. In a study of patients 60 years or older,
who did not receive concomitant administration of narcotics, 2 to 3
mg (0.02 to 0.05 mg/kg) of VERSED produced adequate sedation during
the preoperative period. The dose of 1 mg IM VERSED may suffice for
some older patients if the anticipated intensity and duration of
sedation is less critical. Intravenous - VERSED 1 mg/mL formulation
is recommended for sedation/anxiolysis/amnesia for procedures to
facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL
formulations may be diluted with 0.9% sodium chloride or 5%
dextrose in water. 1. Healthy Adults Below the Age of 60: Titrate
slowly to the desired effect (eg, the initiation of slurred
speech). Some patients may respond to as little as 1 mg. No more
than 2.5 mg should be given over a period of at least 2 minutes. A
total dose greater than 5 mg is not usually necessary to reach the
desired endpoint. If narcotic premedication or other CNS
depressants are used, patients will require approximately 30% less
VERSED than unpremedicated patients. 2. Patients Age 60 or Older,
and Debilitated or Chronically Ill Patients: Titrate slowly to the
desired effect (eg, the initiation of slurred speech). Some
patients may respond to as little as 1 mg. No more than 1.5 mg
should be given over a period of no less than 2 minutes. If
additional titration is necessary, it should be given at a rate of
no more than 1 mg over a period of 2 minutes, waiting an additional
2 or more minutes each time to fully evaluate the sedative effect.
Total doses greater than 3.5 mg are not usually necessary.
Epileptic fit: 10 mg intranasally or as buccal. NIMETAZEPAN MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg 0.08330
NITRAZEPAM Nitrazepam shortens the time required to fall asleep and
lengthens
the duration of this sleep. Typically, it may work within an hour
and allow the individual to maintain sleep for 4 to 6 hours. It is
no longer available in the United States. NORDAZEPAM Defined Daily
Dose - 15 mg, No data available from FDA. OXAZEPAM Mild to moderate
anxiety, with associated tension, irritability, agitation or
related symptoms of functional origin or secondary to organic
disease: 10 to 15 mg, 3 or 4 times daily. Severe anxiety syndromes,
agitation, or anxiety associated with depression: 15 to 30 mg, 3 or
4 times daily. Older patients with anxiety, tension, irritability,
and agitation: Initial dosage - 10 mg, 3 times daily. If necessary,
increase cautiously to 15 mg, 3 or 4 times daily. Alcoholics with
acute inebriation, tremulousness, or anxiety on withdrawal: 15 to
30 mg, 3 or 4 times daily. OXAZOLAM 20 mg is equivalent to 10 mg of
Diazepam. MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
body weight (bw)/day based upon an average adult weighing 60 kg
1.0000 PINAZEPAM MRTD (Maximum Recommended Therapeutic Dose) in
mg/kg- body weight (bw)/day based upon an average adult weighing 60
kg 0.33300 PRAZEPAM MRTD (Maximum Recommended Therapeutic Dose) in
mg/kg- body weight (bw)/day based upon an average adult weighing 60
kg 1.00000 QUAZEPAM The recommended initial dose is 15 milligrams
daily. Your doctor may later reduce this dosage to 7.5 milligrams.
TEMAZEPAM While the recommended usual adult dose is 15 mg before
retiring, 7.5 mg may be sufficient for some patients, and others
may need 30 mg. In transient insomnia, a 7.5 mg dose may be
sufficient to improve sleep latency. In elderly and/or debilitated
patients it is recommended that therapy be initiated with 7.5 mg
until individual responses are determined. TETRAZEPAM Defined Daily
Dose - 100 mg, No data available from FDA. TOFISOPAM Tofisopam is
not approved for sale in the US or Canada. However, Vela
Pharmaceuticals of New Jersey is developing the D- enantiomer
(dextofisopam) as a treatment for IBS. TRIAZOLAM The recommended
dose for most adults is 0.25 mg before retiring. dose of 0.125 mg
may be found to be sufficient for some patients (e.g., low body
weight). A dose of 0.5 mg should be used only for exceptional
patients who do not respond adequately to a trial of a lower dose
since the risk of several adverse reactions increases with the size
of the dose administered. A dose of 0.5 mg should not be exceeded.
In geriatric and/or debilitated patients the recommended dosage
range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125
mg in this group and the 0.25 mg dose should be used only for
exceptional patients who do not respond to a trial of the lower
dose. A dose of 0.25 mg should not be exceeded in these patients.
HORMONES/ ESTROGENS See other columns. Hormone-Containing
Contraceptives General Dosing Information: CONTRACEPTIVES include:
ethinyl Combination contraceptives are those containing both
estrogen and estradiol and progesterone. mestranol. Several types
of combination birth control pills exist, including PROGESTERONES
monophasic pills, biphasic pills, triphasic pils, and 91-day cycle
include: pills. Norethynodrel, USE: Starting at the beginning of
the pill pack, take one each day a norethindrone, approximately the
same time every day to increase efficacy. norethindrone WHEN TO
BEGIN: The following regimens may be used when acetate, first
starting on birth control pills: norgestimate, Taking one pill each
day, starting on the fifth day after the desogestrel, onset of
menses and continuing for 21 or 28 days. ethyndiol Beginning pills
on the first day of the menstrual period. diacetate, Beginning on
the first Sunday after the menstrual period norgestrel, starts.
levonorgestrel, 21-DAY PILL CONTAINER: Take one pill daily for 21
days, stop drospirenone. for 7 days, then resume taking the pills
with a new container of pills 28-DAY PILL CONTAINER: Start with the
first pill in the container and swallow one daily for 28 days. Do
not stop taking the pills. The last 7 ae usually placebos. 91-DAY
PILL CONTAINER: One pill is taken daily for 12 weeks, followed by
one week of inactive pills. A menstrual period occurs during the
week of inactive pills, so women on this regimen have a period only
once every three months. Monophasic Pills: Alesse, Brevicon,
Demulen, Desogen, Levlen, Levlite, Loestrin, Microgestin, Modicon,
Necon, Nelova, Nordette, Norinyl, Ortho-Cept, Ortho-Cyclen,
Ortho-Novum, Ovcon, Ovral, Yasmin, Zovia. Monophasic pills have a
constant dose of estrogen and progestin in each of the hormonally
active pills through the entire cycle (21 day of ingesting active
pills). Several of the brands listed above may be available in
several strengths of estrogen or progesterone, from which doctors
choose according to a woman's individual needs. Biphasic Pills:
Jenest, Mircette, Necon 10/11, Nelova 10/11, and Ortho-Novum 10/11
Biphasic Pills typically contain two different progesterone doses.
The progesterone dose is increased about halfway through the cycle.
Triphasic Pills: Cyclessa, Estrostep, Ortho-Novum 7/7/7, Ortho Tri
Cyclen, Ortho Tri-Cyclen LO, Tri-Levlen, Tri-Norinyl, Triphasil,
Trivora Triphasic pills gradually increase the dose of estrogen
during the cycle (some pills also increase the progesterone dose).
Three different increasing pill doses are contained in each cycle.
Ninety-One Day BCP: Levonorgestrel/ethynl estradiol (Seasonale)
These pills are monophasic birth control pills that have been
approved for use on a daily basis for 84 days without interruption.
Users have fewer schedules menstrual cycles (only 1 period every 3
months). Topical Contraceptive Patch: Norelgestromin/ethinyl
estradiol (Ortho Evra) A new patch is applied on the same day of
the week, each week for three weeks in a row. The first patch is
applied on either the first day of the menstrual period or on the
Sunday following menses. Or the fourth week, no patch is applied.
Another 4-week cycle is started by applying a new patch following
the 7-day patch free period. Long-Acting, Injectable,
Progesterone-Only Contraceptives: Medroxyprogesterone acetate
(Depo-Provera) The first injection is given within five days
following the onset of menstruation. After that, an injection is
needed every 11-13 weeks. Unlike pills, the injection works right
away. Progesterone-Only Pills: Norethindrone (Nor-QD)
Progesterone-only pills, also known as mini-pills, are not used
widely in the US. POPs are ingested once daily, every day. They may
be started on any day, and there are no pill-free days or different
colored pills to track. Since progesterone is the only hormonal
ingredient, estrogen-related side effects are avoided. Vaginal
Ring: Etonogestrel/ethinyl estradiol (NuvaRing) The ring is
self-inserted into the vagina. Exact positioning is not required
for it to be effective. The vaginal ring must be inserted within 5
days of the onset of the menstrual period, even if bleeding is
still occurring. During the first cycle, an additional method of
contraception is recommended. The ring remains in place
continuously for three weeks. It is removed for one week. The nex
ring is then inserted one week after the last ring was removed.
NON- CHLORAL HYDRATE The usual hypnotic dose is 500 mg to 1 g,
taken 15 to 30 minutes BENZODIAZEPINE before bedtime or 1/2 hour
before surgery. The usual sedative dose i ANXIOLYTICS 250 mg three
times daily after meals. Generally, single doses or SEDATIVES daily
dosage should not exceed 2 g. HYPNOTICS CHLORAL BETAINE Chloral
betaine 707 mg (chloral hydrate 414 mg) TRANQUILIZERS Dose: 1-2
tablets with water or milk at bedtime, max. 5 tablets (2 g chloral
hydrate) daily CLOMETHIAZOLE (or MRTD (Maximum Recommended
Therapeutic Dose) in mg/kg- CHLOMETHIAZOLE) body weight (bw)/day
based upon an average adult weighing 60 kg 6.40000 DIPHENHYDRAMINE
Adults: 25 to 50 mg three or four times daily. Children (over 20
lb): 12.5 to 25 mg three to four times daily. Maximum daily dosage
not to exceed 300 mg. ETHCHLORVYNOL Due to the problems it can
cause, it is unusual for ethchlorvynol to be prescribed for periods
exceeding seven days. PROMETHIAZINE. Administration of 12.5 to 25
mg Phenergan by the oral route or by rectal suppository at bedtime
will provide sedation in children. Adults usually require 25 to 50
mg for nighttime, presurgical, or obstetrical sedation. ZALPELON
The recommended dose of Sonata for most nonelderly adults is 10 mg.
(imidazopyridine) For certain low weight individuals, 5 mg may be a
sufficient dose. Although the risk of certain adverse events
associated with the use of Sonata appears to be dose dependent, the
20 mg dose has been shown to be adequately tolerated and may be
considered for the occasional patient who does not benefit from a
trial of a lower dose. ZOLPIDEM The recommended dose for adults is
10 mg immediately before (pyrazolopyrimidine) bedtime, indicated
for the short-term treatment of insomnia. ZOPICLONE The usual dose
is 7.5 mg at bedtime. This dose should not be exceeded. Depending
on clinical response and tolerance, the dose may be lowered to 3.75
mg. Geriatrics: In the elderly and/or debilitated patient an
initial dose of 3.75 mg at bedtime is recommended. The dose may be
increased to 7.5 mg if the starting dose does not offer adequate
therapeutic effect. STIMULANTS CAFFEINE Caffeine Oral is used to
treat the following: Absence of Breathing in the Newborn Caffeine
Oral may also be used to treat: Drowsiness, Low Energy Caffeine
citrate is indicated for the short term treatment of apnea of
prematurity in infants between 28 and <33 weeks gestational age.
Caffeine Citrate: Loading Dose - 20 mg/kg Maintenance Dose - 5
mg/kg NICOTINE NICOTROL Inhaler is indicated as an aid to smoking
cessation for the relief of nicotine withdrawal symptoms. NICOTROL
Inhaler therapy is recommended for use as proof of a comprehensive
behavioral smoking cessation program. It it supplied as 42
cartridges each containing 10 mg (4 mg is delivered) nicotine.
Initial Treatment: Up to 12 Weeks: 6-16 cartridges/day Gradual
Reduction (if needed) - 6-12 Weeks: No tapering strategy has been
shown to be superior to any other in clinical studies. OTC
DEXTROMETHORPHAN Now prescription only in the United States.
MEDICATIONS MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
body weight (bw)/day based upon an average adult weighing 60 kg
2.00000 MISCELLANEOUS GHB It has been used as a general anesthetic,
and a hypnotic in the Gamma-hydroxybutyrate treatment of insomnia.
GHB has also been used to treat clinical depression, and improve
athletic performance. In the US, the FDA permits the use of GHB to
reduce the number of cataplexy attacks in patients with narcolepsy.
In Italy, GHB is used for the treatment of alcoholism (50 to 100 mg
per kg per day, in 3 or more divided doses), both for acute alcohol
withdrawal and medium to long term detoxification. LD50 of GHB is
estimated to be between 1100 mg/kg and 2000 mg/kg in rodents and is
almost certainly lower in humans. MEPROBROMATE Meprobromate is
available in 200 mg and 400 mg tablets for oral administration.
Symptoms of meprobromate overdose include coma, drowsiness, loss of
muscle control, severly impaired breathing, shock, sluggishness,
and unresponsiveness. Death has been reported with ingestion of as
little as 12 g of meprobromate and survival with as much as 40 g.
METHQUALONE In the United States, the marketing of methaqualone
pharmaceutical products stopped in 1984, and methaqualone was
transferred to Schedule I of the CSA. NITROUS OXIDE Nitrous Oxide
is a weak general anesthetic, and is generally not used alone. It
has a very low short-term toxicity and is an excellent analgesic.
In general anesthesia it is often used in a 2:1 ratio with oxygen
in addition to more powerful general anesthetic agents. Possession
of nitrous oxide is illegal in most localities in the United States
for the purposes of inhaling or ingesting if not under the care of
a physician or dentist. PCP Not available for medicinal use.
Phencyclidine HERBAL VALERIAN ROOT Dosing not regulated/approved by
FDA. MEDICINALS (Valeriana officinalis, Large doses are known to
cause withdrawal symptoms when Valerianaceae) stopped, as it is
mildly addictive. Those with liver disease are advised not to use
valerian. Valerian is the source of valeric acid. SALVINORIN A
N.A.
Salvinorin A is the main active Salvinorin A is a dissociative
hallucinogenic compound that is psychotropic constituent of the
active at the extremely low doses of 0.2-0.5 mg, second only to
plant Salvia divinorum LSD in quantitative potency, making it the
most potent naturally (diviner's sage, Mexican mint). occurring
drug known to date. A dose of 200 to 500 micrograms produces
profound hallucinations when smoked. Its' effects in the open field
test in mice and loco motor activity tests in rats are similar to
mescaline. ST. JOHN'S WORT The dosage of St John's wort
preparations vary greatly between Refers to the species Hypericum
formulations, due to variability in the plant source and
preparation perforatum. processes. The doses of St. John's wort
extract used in clinical trials generally range from 350 to 1800 mg
daily (equivalent to 0.4 to 2.7 mg hypericin depending on the
preparation). The recommended dosage for various forms of St John's
wort as recommended by the British Herbal Medicine Association
Scientific Committee (1983) are as follows: dried herb: 2-4 g or by
infusion three times daily liquid extract 2-4 mL (1:1 in 25%
alcohol) three times daily tincture 2-4 mL (1:10 in 45% alcohol)
three times daily ANTI- CITALOPRAM HBR Celexa (citalopram HBr) is
indicated for the treatment of DEPRESSION (CELEXA) depression.
DRUGS Celexa (citalopram HBr) should be administered at an initial
dose of 20 mg once daily, generally with an increase to a dose of
40 mg/ day. Dose increases should usually occur in increments of 20
mg at intervals of no less than one week ESCITALOPRAM OXALATE
LEXAPRO (escitalopram) is indicated for the treatment of major
LEXAPRO .TM. depressive disorder and Generalized Anxiety Disorder
(GAD). The recommended dose of LEXAPRO is 10 mg once daily.
FLUOXETINE Prozac is indicated for the treatment of: Major
Depressive Disorder: HYDROCHLORIDE a dose of 20 mg/day,
administered in the morning, is recommended as the initial dose.
The maximum fluoxetine dose should not exceed 80 mg/day. Obsessive
Compulsive Disorder: a dose of 20 mg/day administered in the
morning, is recommended as the initial dose. The maximum fluoxetine
dose should not exceed 80 mg/day. Bulimia Nervosa: the recommended
dose is 60 mg/day, administered in the morning. Panic Disorder:
Treatment should be initiated with a dose of 10 mg/day. After 1
week, the dose should be increased to 20 mg/day. PAROXETINE Major
Depressive Disorder: The recommended initial dose is HYDROCHLORIDE
20 mg/day. Some patients not responding to a 20-mg dose may benefit
from dose increases, in 10-mg/day increments, up to a maximum of 50
mg/day. Obsessive Compulsive Disorder: The recommended dose of
PAXIL in the treatment of OCD is 40 mg daily. Patients should be
started on 20 mg/day and the dose can be increased in 10-mg/day
increments. The maximum dosage should not exceed 60 mg/day. Panic
Disorder: The target dose of PAXIL in the treatment of panic
disorder is 40 mg/day. The maximum dosage should not exceed 60
mg/day. Social Anxiety Disorder: The recommended and initial dosage
is 20 mg/day. Generalized Anxiety Disorder: The recommended
starting dosage and the established effective dosage is 20 mg/day.
Posttraumatic Stress Disorder: The recommended starting dosage and
the established effective dosage is 20 mg/day. FLUVOXAMINE MALEATE
Fluvoxamine is indicated in the treatment of depression and for
(LUVOX). Obsessive Compulsive Disorder (OCD). The recommended
starting dose for LUVOX Tablets in adult patients is 50 mg,
administered as a single daily dose at bed time. The maximum
therapeutic dose should not to exceed 300 mg per day. SERTRALINE
Major Depressive Disorder and Obsessive-Compulsive Disorder:
HYDROCHLORIDE ZOLOFT treatment should be administered at a dose of
50 mg once daily. Panic Disorder, Posttraumatic Stress Disorder and
Social Anxiety Disorder: ZOLOFT treatment should be initiated with
a dose of 25 mg once daily. After one week, the dose should be
increased to 50 mg once daily. Premenstrual Dysphoric Disorder:
ZOLOFT treatment should be initiated with a dose of 50 mg/day,
either daily throughout the menstrual cycle or limited to the
luteal phase of the menstrual cycle, depending on physician
assessment. AMITRIPTYLINE For the relief of symptoms of depression.
Endogenous depression is more likely to be alleviated than are
other depressive states. Oral Dosage: 75 mg of amitriptyline HCl a
day in divided doses. If necessary, this may be increased to a
total of 150 mg per day. Intramuscular Dosage: Initially, 20 to 30
mg (2 to 3 ml) four times a day. DESIPRAMINE Desipramine
hydrochloride is indicated for relief of symptoms in HYDROCHLORIDE
various depressive syndromes, especially endogenous depression. The
usual adult dose is 100 to 200 mg per day. Dosages above 300 mg/day
are not recommended. Not recommended for use in children.
NORTRIPTYLINE Nortriptyline HCl is indicated for the relief of
symptoms of depression. Endogenous depressions are more likely to
be alleviated than are other depressive states. It is not
recommended for children Usual Adult Dose - 25 mg three or four
times daily. Doses above 150 mg/day are not recommended. Elderly
and Adolescent Patients - 30 to 50 mg/day, in divided doses, or the
total daily dosage may be given once a day. DULOXETINE Cymbalta is
indicated for the treatment of major depressive disorder
HYDROCHLORIDE (MDD) and pain associated with diabetic peripheral
neuropathy. Major Depressive Disorder: Cymbalta should be
administered at a total dose of 40 mg/day Diabetic Peripheral
Neuropathic Pain: Cymbalta should be administered at a total dose
of 60 mg/day given once a day VENLAFAXINE Effexor (venlafaxine
hydrochloride) is indicated for the treatment of Effexor major
depressive disorder. The recommended starting dose for Effexor is
75 mg/day, up to a maximum of 375 mg/day, generally in three
divided doses PHENELZINE SULFATE The usual starting dose of Nardil
is one tablet (15 mg) three times a day. Maintenance dose may be as
low as one tablet, 15 mg, a day or every other day, and should be
continued for as long as is required. TRANYLCYPROMINE For the
treatment of Major Depressive Episode Without (Parnate)
Melancholia. The usual effective dosage is 30 mg per day, usually
given in divided doses; may be extended to a maximum of 60 mg per
day. When tranylcypromine is withdrawn, monoamine oxidase activity
is recovered in 3 to 5 days, although the drug is excreted in 24
hours. MIRTAZEPINE Indicated for the treatment of major depressive
disorder. The recommended starting dose for REMERON .RTM.
(mirtazapine) Tablets is 15 mg/day, up to a maximum of 45 mg/day.
NEFAZODONE SERZONE (nefazodone hydrochloride) is indicated for the
HYDROCHLORIDE treatment of depression. When deciding among the
alternative SERZONE .RTM. treatments available for this condition,
the prescriber should consider the risk of hepatic failure
associated with SERZONE treatment. The recommended starting dose
for SERZONE (nefazodone hydrochloride) is 200 mg/day TRAZODONE
DESYREL is indicated for the treatment of depression. HYDROCHLORIDE
An initial dose of 150 mg/day in divided doses is suggested, up to
DESYREL but not in excess of 600 mg/day in divided doses. BUPROPION
WELLBUTRIN is indicated for the treatment of depression.
HYDROCHLORIDE The usual adult dose is 300 mg/day, given 3 times
daily. WELLBUTRIN (bupropion WELLBUTRIN should be discontinued in
patients who do not hydrochloride) demonstrate an adequate response
after an appropriate period of treatment at 450 mg/day. When
Wellbutrin is used in combination with an SSRI to offset sexual
side effects, the usual dose is 75 mg per day. Isocarboxazid The
maximum daily dose of isocarboxazid is 60 mg. Moclobemide
Depression: The initial dose is 300 mg daily in 2 or 3 divided
doses. Social Phobia: The recommended dose is 600 mg daily in 2 or
3 divided doses. A single 300 mg dose of moclobemide inhibits 80%
of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B
(MAO-B), blocking the decomposition of norepinephrine, serotonin
and, to a lesser extent, dopamine. No reuptake inhibition on any of
the neurotransmitters occurs. Selegiline 10 mg per day administered
as divided doses of 5 mg each. NEUROSTEROID 5-ALPHA- FINASTERIDE
The recommended dosage is 1 mg orally once per day. It may be
INHIBITORS REDUCTASE administered with or without meals. INHIBITORS
An alternate dosage of 5 mg orally once per day is also included.
It may be administered with or without meals. In general, daily use
for three months or more is necessary before benefit is observed.
Continued use is recommended to sustain benefit, which should be
re-evaluated periodically. Withdrawal of treatment leads to
reversal of effect within 12 months. In clinical studies, single
doses of finasteride up to 400 mg and multiple doses of finasteride
up to 80 mg/day for three months did not result in adverse
reactions. DUTASTERIDE The recommended therapeutic dose of
dutasteride is 0.5 mg taken orally once per day. Dutasteride
pharmacokinetics has not been investigated in subjects less than 18
years of age. No dose adjustment is necessary in the elderly. In
volunteer studies, single doses of dutasteride up to 40 mg (80
times the therapeutic dose) for 7 days have been administered
without significant safety concerns. In a clinical study, daily
doses of 5 mg (10 times the therapeutic dose) were administered to
60 subjects for 6 months with no additional adverse effects to
those seen at therapeutic does of 0.5 mg. SAW PALMETTO
Tablets/Capsules. A dose of 160 mg twice daily or 320 milligrams
daily (containing 80% to 90% liposterolic content) for up to 11
months has been taken by mouth. Higher doses may be used under
medical supervision. Berries. A dose of one to two grams of ground,
dried, or whole berries daily has been taken by mouth. Tincture. A
dose of two to four milliliters (1:4) three times daily has been
taken by mouth. Fluid Extract of Berry Pulp. A dose of one to two
milliliters (1:1) three times daily has been taken by mouth. Rectal
Suppositories. A dose of 640 milligrams once daily has been used.
Rectal use of saw palmetto is no better than taking saw palmetto by
mouth. Tea. Tea made from berries may not be effective because the
proposed active ingredient does not dissolve in water.
SPIRONOLACTONE Treatment protocols may involve continuous
spironolactone use at 50 mg to 200 mg per day or cyclic use; for
example, 50 mg or 100 mg twice daily from the 4.sup.th to the
22.sup.nd day of the menstrual cycle. Numerous treatment protocols
involving spironolactone have been used in different studies, but
no particular treatment approach has been shown to be significantly
superior. 3-ALPHA INDOMETHACIN Indomethacin can be administered in
the form of capsules (25 mg REDUCTASE and 50 mg); sustained-release
capsules (75 mg); a suspension INHIBITORS (25 mg/ml); or a
suppository (50 mg). The recommended dose for adults is 50-200 mg
per day split into 2-3 doses. CLASS OF FLUMAZENIL ROMAZICON is
indicated for the complete or partial reversal of COMPOUNDS
(Romazicon) the sedative effects of benzodiazepines in cases where
general THAT anesthesia has been induced and/or maintained with
SELECTIVELY benzodiazepines, where sedation has been produced with
MODULATES benzodiazepines for diagnostic and therapeutic
procedures, and for GABA.sub.A the management of benzodiazepine
overdose. Reversal of RECEPTORS Conscious Sedation: The recommended
initial dose of ROMAZICON is 0.2 mg (2 mL) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an additional 45
seconds, a second dose of 0.2 mg (2 mL) can be injected and
repeated at 60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 1 mg (10 mL).
Reversal of General Anesthesia in Adult Patients: The recommended
initial dose of ROMAZICON is 0.2 mg (2 mL) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an additional 45
seconds, a further dose of 0.2 mg (2 mL) can be injected and
repeated at 60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 1 mg (10 mL).
Management of Suspected Benzodiazepine Overdose in Adult Patients:
the recommended initial dose of ROMAZICON is 0.2 mg (2 mL)
administered intravenously over 30 seconds. If the desired level of
consciousness is not obtained after waiting 30 seconds, a further
dose of 0.3 mg (3 mL) can be administered over another 30 seconds.
Further doses of 0.5 mg (5 mL) can be administered over 30 seconds
at 1-minute intervals up to a cumulative dose of 3 mg. MILTIRONE
The below doses are based on scientific research, publications,
traditional use, or expert opinion. Many herbs and supplements have
not been thoroughly tested, and safety and effectiveness may not be
proven. You should read product labels, and discuss doses with a
qualified healthcare provider before starting therapy.
Standardization: There is no widely accepted standardization or
well-studied dosing of miltirone, and many different doses are used
traditionally. Adults (18 years and older): By mouth. Oral dosing
has not been studied in well-conducted trials in humans, and
therefore no specific dose can be recommended. By injection: In
research from the 1970s, an 8 milliliter injection of miltirone (16
grams of the herb) was given intravenously (diluted in 500
milliliters of a 10% glucose solution) for up to four weeks for
ischemic stroke. Safety and effectiveness have not been established
for this route of administration and it cannot not recommended at
his time. Children (younger than 18 years): There is not enough
scientific evidence to recommend the safe use of danshen in
children, and it should be avoided due to potentially serious side
effects. FLAVONOIDS They have been classified N.A. according to
their chemical structure, and are usually subdivided into 6
subgroups: Flavonols, including Quercetin, Kaempferol, Myricetin,
Isorhamnetin Flavones, including Luteolin, Apigenin Flavanones,
including Hesperetin, Naringenin, Eriodictyol Flavan-3-ols,
including (+)- Catechin, (+)-Gallocatechin, (-)- Epicatechin, (-)-
*Epigallocatechin, (-)- Epicatechin 3-gallate, (-)-
Epigallocatechin 3-gallate, Theaflavin, Theaflavin 3- gallate,
Theaflavin 3'-gallate, Theaflavin 3,3' digallate, Thearubigins
Isoflavones, including Genistein, Daidzein, Glycitein
Anthocyanidins, including Cyanidin, Delphinidin, Malvidin,
Pelargonidin, Peonidin, Petunidin DOPAMINE ERGOT The dose of
bromocriptine will be different for different patients. AGONISTS
ALKALOIDS Follow your doctor's orders or the directions on the
label. The following information includes only the average doses of
bromocriptine. If your dose is different, do not change it unless
your doctor tells you to do so. The number of capsules or tablets
that you take depends on the strength of the medicine. Also, the
number of doses you take each day, the time allowed between doses,
and the length of time you take the medicine depend on the medical
problem for which you are taking bromocriptine. For oral dosage
forms (capsules and tablets): For infertility, male hormone problem
(male hypogonadism), starting the menstrual cycle (amenorrhea), or
stopping abnormal milk secretion from nipples (galactorrhea):
Adults and teenagers 15 years of age or older - At first, 1.25 to
2.5 milligrams (mg) once a day taken at bedtime with a snack. Then
your doctor may change your dose by 2.5 mg every three to seven
days as needed. Doses greater than 5 mg a day are taken in divided
doses with meals or at bedtime with a snack. Teenagers less than 15
years of age and children - Use and dose must be determined by your
doctor. For lowering growth hormone (acromegaly): Adults and
teenagers 15 years of age or older - At first, 1.25 to 2.5
milligrams (mg) once a day taken at bedtime with a snack for three
days. Then your doctor may change your dose by 1.25 or 2.5 mg every
three to seven days as needed. Doses greater than 5 mg are divided
into smaller doses and taken with meals or at bedtime with a snack.
Teenagers less than 15 years of age and children - Use and dose
must be determined by your doctor. For Parkinson's disease: Adults
and teenagers 15 years of age or older - At first, 1.25 milligrams
(mg) one or two times a day taken with meals or at bedtime with a
snack. Then your doctor may change your dose over several weeks as
needed. Teenagers less than 15 years of age and children - Use and
dose must be determined by your doctor. For pituitary tumors:
Adults and teenagers 15 years of age or older - At first, 1.25
milligrams (mg) two or three times a day taken with meals. Then
your doctor may change your dose over several weeks as needed.
Teenagers less than 15 years of age and children - Use and dose
must be determined by your doctor. PRESCRIPTION METHYLPHENIDATE
Methylphendiate comes in 5 mg, 10 mg and 20 mg tablets. STIMULANTS
ADULTS Tablets: Administer in divided doses, 2 or 3 times daily,
preferably 30 to 45 minutes before meals. Average dosage is 20 to
30 mg daily. Some patient may require 40 to 60 mg daily. In others,
10 to 15 mg daily will be adequate. FOR CHILDREN, DOSAGES SHOULD BE
INITIATED IN INCREMENTS Days 1-3: One 5 mg tablet per day Days 4-6:
Two 5 mg tablets per day Add one pill every fourth day until a
dosage of 20 mg per day is achieved. Daily dosage above 60 mg is
not recommended. ADDERALL. Attention Deficit Disorder with
Hyperactivity: Not recommended for children under 3 years of age.
In children from 3 to 5 years of age, start with 2.5 mg daily;
daily dosage may be raised in increments of 2.5 mg at weekly
intervals until optimal response is obtained. In children 6 years
of age and older, start with 5 mg once or twice daily; daily dosage
may be raised in increments of 5 mg at weekly intervals until
optimal response is obtained. Only in rare cases will it be
necessary to exceed a total of 40 mg per day. Give first dose on
awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
Where possible, drug administration should be interrupted
occasionally to determine if there is a recurrence of behavioral
symptoms sufficient to require continued therapy. Narcolepsy: Usual
dose 5 mg to 60 mg per day in divided doses, depending on the
individual patient response. Narcolepsy seldom occurs in children
under 12 years of age; however, when it does, dextroamphetamine
sulfate may be used. The suggested initial dose for patients aged
6-12 is 5 mg daily; daily dose may be raised in increments of 5 mg
at weekly intervals until optimal response is obtained. In patients
12 years of age and older, start with 10 mg daily; daily dosage may
be raised in increments of 10 mg at weekly intervals until optimal
response is obtained. If bothersome adverse reactions appear (e.g.,
insomnia or anorexia), dosage should be reduced. Give first dose on
awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
DEXEDRINE Narcolepsy. Usual dose 5 to 60 mg per day in divided
doses, depending on the individual patient response. Narcolepsy
seldom occurs in children under 12 years of age; however, when it
does Dexedrine (dextroamphetamine sulfate) may be used. The
suggested initial dose for patients aged 6 to 12 is 5 mg daily;
daily dose may be raised in increments of 5 mg at weekly intervals
until optimal response is obtained. In patients 12 years of age and
older, start with 10 mg daily; daily dosage may be raised in
increments of 10 mg at weekly intervals until optimal response is
obtained. If bothersome adverse reactions appear (e.g. insomnia or
anorexia), dosage should be reduced. Spansule capsules may be used
for once-a-day dosage wherever appropriate. With tablets give first
dose on awakening, additional doses (1 or 2) at intervals of 4 to 6
hours. Attention Deficit Disorder with Hyperactivity. Not
recommended for pediatric patients under 3 years of age. In
pediatric patients from 3 to 5 years of age, start with 2.5 mg
daily, by tablet daily dosage may be raised in increments of 2.5 mg
at weekly intervals until optimal response is obtained. In
pediatric patients 6 years of age and older, start with 5 mg once
or twice daily, daily dosage may be raised in increments of 5 mg at
weekly intervals until optimal response is obtained. Only in rare
cases will it be necessary to exceed a total of 40 mg per day.
Spansule capsules may be used for once-a-day dosage wherever
appropriate. With tablets, give first dose on awakening additional
doses (1 or 2) at intervals of 4 to 6 hours.
* * * * *
References